Fluoro-pyridinone derivatives useful as antibacterial agents

ABSTRACT

The present invention is directed to a new class of hydroxamic acid derivatives, their use as LpxC inhibitors and, more specifically, their use to treat bacterial infections.

This application is a continuation application under 35 U.S.C. §120 ofU.S. Non-Provisional patent application Ser. No. 13/414,057, filed Mar.7, 2012, which claims the priority to U.S. Provisional PatentApplication Ser. No. 61/449,825, filed on Mar. 7, 2011, the disclosuresof which are hereby incorporated by reference in their entirety and forall purposes.

BACKGROUND OF THE INVENTION

Infection by Gram-negative bacteria such as Pseudomonas aeruginosa,Extended Spectrum β-lactamase producing (ESBL) Entgerobacteriaceae, andAcinetobacter baumannii is a major health problem, especially in thecase of hospital-acquired infections. In addition, there is anincreasing level of resistance to current antibiotic therapies, whichseverely limits treatment options. For example, in 2002, 33% ofPseudomonas aeruginosa infections from intensive care units wereresistant to fluoroquinolones, while resistance to imipenem was 22% (CID42: 657-68, 2006). In addition, multi-drug resistant (MDR) infectionsare also increasing; in the case of Pseudomonas aeruginosa, MDRincreased from 4% in 1992 to 14% in 2002 (Biochem Pharm 71: 991, 2006).

Gram-negative bacteria are unique in that their outer membrane containslipopolysaccharide (LPS), which is crucial for maintaining membraneintegrity, and is essential for bacterial viability (reviewed in Ann.Rev. Biochem 76: 295-329, 2007). The major lipid component of LPS isLipid A, and inhibition of Lipid A biosynthesis is lethal to bacteria.Lipid A is synthesized on the cytoplasmic surface of the bacterial innermembrane via a pathway that consists of nine different enzymes. Theseenzymes are highly conserved in most Gram-negative bacteria. LpxC[UDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase] is theenzyme that catalyzes the first committed step in the Lipid Abiosynthetic pathway, the removal of the N-acetyl group ofUDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine. LpxC is aZn²⁺-dependent enzyme that has no mammalian homologue, making it a goodtarget for the development of novel antibiotics. Several inhibitors ofLpxC with low nM affinity have been reported (Biochemistry 45: 7940-48,2006).

SUMMARY OF THE INVENTION

A new class of LpxC inhibitors has been discovered. These compounds, ortheir pharmaceutically acceptable salts, can be represented by Formula Ibelow:

in which:

-   R¹ is represented by C₁-C₃ alkyl;-   R² is represented by hydrogen or C₁-C₃ alkyl;-   R³ is represented by hydrogen, halogen, hydroxy, cyano, C₁-C₃alkyl,    C₁-C₃alkoxy, trifluoromethyl or trifluoromethoxy;-   T is represented by ethynyl, optionally substituted (C₆-C₁₀)aryl or    optionally substituted heteroaryl;-   D is absent, or is represented by —(CH₂)_(r)—,    —(CH₂)_(n)—O—(CH₂)_(p)—, or a bond;-   r is represented by the integer 1, 2, or 3;-   n and p are each independently represented by the integer 0, 1, or    2;-   E is absent, or is represented by a substituent selected from the    group consisting of:    -   i) (C₃-C₁₀)cycloalkyl, optionally substituted;    -   ii) (C₆-C₁₀)aryl optionally substituted;    -   iii) heteroaryl, optionally substituted; and    -   iv) heterocyclic, optionally substituted;-   with the proviso that:    -   1) if E is absent, then D is also absent;    -   2) T is not represented by unsubstituted phenyl; when E and D        both are absent, R³ is hydrogen and R¹ and R² are each methyl.

The compounds of Formula I exhibit antibacterial activity, especiallyagainst Gram-negative organisms. They may be used to treat bacterialinfections in mammals, especially humans. The compounds may also be usedfor veterinary applications, such as treating infections in livestockand companion animals.

The compounds of Formula I are useful for treating a variety ofinfections; especially Gram-negative infections including nosocomialpneumonia, urinary tract infections, systemic infections (bacteremia andsepsis), skin and soft tissue infections, surgical infections,intraabdominal infections, lung infections (including those in patientswith cystic fibrosis), Helicobacter pylori (and relief of associatedgastric complications such as peptic ulcer disease, gastriccarcinogenesis, etc.), endocarditis, diabetic foot infections,osteomyelitis, and central nervous system infections.

In order to simplify administration, the compounds will typically beadmixed with at least one excipient and formulated into a pharmaceuticaldosage form. Examples of such dosage forms include tablets, capsules,solutions/suspensions for injection, aerosols for inhalation,cream/ointments for topical, otic or ophthalmic use, andsolutions/suspensions for oral ingestion.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are only being utilized to expediteits review by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplification

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

-   -   a. “C₁-C₃ alkyl” refers to a branched or straight chained alkyl        group containing from 1 to 3 carbon atoms, such as methyl,        ethyl, n-propyl, or isopropyl, etc.    -   b. “C₁-C₃ alkoxy” refers to a straight or branched chain alkoxy        group containing from 1 to 3 carbon atoms, such as methoxy,        ethoxy, n-propoxy, isopropoxy, etc.    -   c. “halogen” refers to a chlorine, fluorine, iodine, or bromine        atom.    -   d. “C₁-C₆ alkyl” refers to a branched or straight chained alkyl        group containing from 1 to 6 carbon atoms, such as methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc.    -   e. “C₁-C₆ alkyl, optionally substituted” refers to a branched or        straight chained alkyl group containing from 1 to 6 carbon        atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,        isobutyl, pentyl, etc. Such an alkyl group may be optionally        substituted, in which up to 3 hydrogen atoms are replaced by a        substituent selected from the group consisting of halogen,        cyano, sulfonamide, imino, —OR⁴, —SR⁴, and —NR⁴R⁵ in which R⁴        and R⁵ are each independently represented by hydrogen or C₁—C₃        alkyl.    -   f. “C₁-C₆ alkoxy” refers to a straight or branched chain alkoxy        group containing from 1 to 6 carbon atoms, such as methoxy,        ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy,        etc.    -   g. “C₁-C₆ alkoxy, optionally substituted” refers to a straight        or branched chain alkoxy group containing from 1 to 6 carbon        atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,        isobutoxy, pentoxy, etc. Such an alkoxy group may be optionally        substituted, in which up to 3 hydrogen atoms are replaced by a        substituent selected from the group consisting of halogen,        cyano, sulfonamide, imino, —OR⁴, —SR⁴, and —NR⁴R⁵ in which R⁴        and R⁵ are each independently represented by hydrogen or C₁-C₃        alkyl.    -   h. “(C₆-C₁₀)aryl” means a cyclic, aromatic hydrocarbon        containing from 6 to 10 carbon atoms. Examples of such aryl        groups include phenyl, naphthyl, etc.    -   i. “(C₆-C₁₀)aryl optionally substituted” means a cyclic,        aromatic hydrocarbon as defined above. Such an aryl moiety may        be optionally substituted with up to 4 non-hydrogen        substituents, each substituent is independently selected from        the group consisting of halogen, cyano, nitro, hydroxy,        (C₁-C₆)alkyl optionally substituted, (C₁-C₆)alkoxy optionally        substituted, trifluoromethyl, trifluoromethoxy, phosphate,        —SO₂NR⁴R⁵, —(CH₂)_(m)—NR⁵—C(O)—R⁴, —(CH₂)_(m)—C(O)—N—R⁴R⁵,        —C(O)—R⁴, —C(O)—O—R⁴, —SR⁴, —SO₂R⁴ and —NR⁴R⁵, in which m, R⁴        and R⁵ are as defined above and each M independently represents        an integer from 0-4. These substituents may be the same or        different and may be located at any position of the ring, that        is chemically permissible. “Phenyl optionally substituted”        refers to a phenyl ring substituted as described above.    -   j. “heteroaryl” refers to an aromatic ring having one, or more,        heteroatoms selected from oxygen, nitrogen and sulfur. More        specifically, it refers to a 5- or 6-membered ring containing 1,        2, 3, or 4 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1        nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2        nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1        sulfur atom. The 5-membered ring has 2 double bonds and the        6-membered ring has 3 double bonds (“hereinafter a “5-to        6-membered heteroaryl”). The term “heteroaryl” also includes        bicyclic groups in which the heteroaryl ring is fused to a        benzene ring, heterocyclic ring, a cycloalkyl ring, or another        heteroaryl ring. Examples of such heteroaryl ring systems        include, but are not limited to, pyrrolyl, furanyl, thienyl,        imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl,        pyrimidinyl, purinyl, quinolinyl, benzofuran, tetrazole,        isoquinolinyl, oxadiazolyl, thiadiazolyl, isothiazolyl,        isoxazolyl, triazolyl, benzo[b]thienyl, 2-, 4-, 5-, 6-, or        7-benzoxazolyl, 7-benzimidazolyl, or benzothiazolyl.    -   k. “heteroaryl, optionally substituted,” refers to a heteroaryl        moiety as defined immediately above, in which up to 4 carbon        atoms of the heteroaryl moiety may be substituted with a        substituent, each substituent is independently selected from the        group consisting of halogen, cyano, nitro, hydroxy, (C₁-C₆)alkyl        optionally substituted, (C₁-C₆)alkoxy optionally substituted,        trifluoromethyl, trifluoromethoxy, phosphate, —SO₂NR⁴R⁵,        —(CH₂)_(m)—N—C(O)—R⁴, —(CH₂)_(m)—C(O)—N—R⁴R⁵, —C(O)—R⁴,        —C(O)—O—R⁴, —SR⁴, —SO₂R⁴ and —NR⁴R⁵, in which m, R⁴ and R⁵ are        as defined above. These substituents may be the same or        different and may be located at any position of the ring, that        is chemically permissible. Any reference to an “optionally        substituted 5- to 6-membered heteroaryl” refers to 5- to        6-membered heteroaryl ring as described in definition j, having        the substitution pattern described immediately above.    -   l. “(C₃-C₁₀) cycloalkyl” refers to a saturated or partially        saturated monocyclic, bicyclic, bridged bicyclic or tricyclic        alkyl radical wherein each cyclic moiety has 3 to 10 carbon        atoms. Examples of such cycloalkyl radicals include cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.    -   m. “(C₃-C₁₀) cycloalkyl” optionally substituted refers to a        (C₃-C₁₀) cycloalkyl moiety as described above. Such a cycloalkyl        group may be optionally substituted, in which up to 4 hydrogen        atoms are replaced by a substituent selected from the group        consisting of halogen, cyano, nitro, hydroxy, (C₁-C₆)alkyl        optionally substituted, (C₁-C₆)alkoxy optionally substituted,        trifluoromethyl, trifluoromethoxy, phosphate, oxo, —SO₂NR⁴R⁵,        —(CH₂)_(m)—NR⁵—C(O)—R⁴, —(CH₂)_(m)—C(O)—N—R⁴R⁵, —C(O)—R⁴,        —C(O)—O—R⁴, —SR⁴, —SO₂R⁴ and —NR⁴R⁵, in which M, R⁴ and R⁵ are        as defined above. These substituents may be the same or        different and may be located at any position of the ring, that        is chemically permissible.    -   n. “(C₃-C₆) cycloalkyl” refers to a cyclopropyl, cyclobutyl,        cyclopentyl or cyclohexyl moiety, any of which may be optionally        substituted as described above, if chemically permissible.    -   o. “heterocycle” or “heterocyclic ring” refers to any 3- or        4-membered ring containing a heteroatom selected from oxygen,        nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10-membered        ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1        sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1        oxygen atom; 2 oxygen atoms in non-adjacent positions; 1 oxygen        and 1 sulfur atom in non-adjacent positions; or 2 sulfur atoms        in non-adjacent positions. The 5-membered ring has 0 to 1 double        bonds, the 6- and 7-membered rings have 0 to 2 double bonds, and        the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double        bonds. The term “heterocyclic” also includes bicyclic groups in        which any of the above heterocyclic rings is fused to a benzene        ring, a cyclohexane or cyclopentane ring or another heterocyclic        ring (for example, indolyl, quinolyl, isoquinolyl,        tetrahydroquinolyl, benzofuryl, dihydrobenzofuryl or        benzothienyl and the like). Heterocyclics include: pyrrolidinyl,        tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl,        piperazinyl, azepane, azocane, morpholinyl, isochromyl,        quinolinyl, tetrahydrotriazine, tetrahydropyrazole,        dihydro-oxathiol-4-yl, dihydro-1H-isoindole,        tetrahydro-oxazolyl, tetrahydro-oxazinyl, thiomorpholinyl,        tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,        octahydrobenzimidazolyl, and octahydrobenzothiazolyl.    -   p. “heterocyclic, optionally substituted” refers to a        heterocyclic moiety as defined immediately above, in which up to        4 carbon atoms of the heterocycle moiety may be substituted with        a substituent, each substituent is independently selected from        the group consisting of halogen, cyano, nitro, hydroxy,        (C₁-C₆)alkyl optionally substituted, (C₁-C₆)alkoxy optionally        substituted, trifluoromethyl, trifluoromethoxy, pentafluoro        sulfonyl, phosphate, oxo, SO₂NR⁴R⁵, —(CH₂)_(m)—N—C(O)—R⁴,        —(CH₂)_(m)—C(O)—N—R⁴R⁵, —C(O)—R⁴, —C(O)—O—R⁴, —SR⁴, —SO₂R⁴ and        —NR⁴R⁵, in which m, R⁴ and R⁵ are as defined above. These        substituents may be the same or different and may be located at        any position of the ring that is chemically permissible. Any        nitrogen atom within such a heterocyclic ring may optionally be        substituted with (C₁-C₆) alkyl, or any other substituent listed        above, if such a substitution is chemically permissible. Any        sulfur atom in the ring may be further substituted with 1 or 2        oxygen atoms (if such a substitution is chemically permissible).    -   q. “therapeutically effective amount” refers to an amount of a        compound of Formula I that, when administered to a patient,        provides the desired effect; i.e., lessening in the severity of        the symptoms associated with a bacterial infection, decreasing        the number of bacteria in the affected tissue, and/or preventing        bacteria in the affected tissue from increasing in number        (localized or systemic).    -   r. “patient” refers to warm blooded animals such as for example,        livestock, guinea pigs, mice, rats, gerbils, cats, rabbits,        dogs, monkeys, chimpanzees, and humans.    -   s. “treat” refers to the ability of the compounds to relieve,        alleviate or slow the progression of the patient's bacterial        infection (or condition) or any tissue damage associated with        the disease.    -   t. “pharmaceutically acceptable” indicates that the substance or        composition must be compatible chemically and/or        toxicologically, with the other ingredients comprising a        formulation, and/or the mammal being treated therewith.    -   u. “isomer” means “stereoisomer” and “geometric isomer” as        defined below.    -   v. “stereoisomer” means compounds that possess one or more        chiral centers and each center may exist in the R or S        configuration. Stereoisomers include all diastereomeric,        enantiomeric and epimeric forms as well as racemates and        mixtures thereof.    -   w. “geometric isomer” means compounds that may exist in cis,        trans, anti, entgegen (E), and zusammen (Z) forms as well as        mixtures thereof.    -   x. Compounds of “Formula I”, “formula I”, “formula (I)” and        “compounds of the invention” are being used interchangeably        throughout the application and should be treated as synonyms.    -   y. The terms “pyridone” and “pyridinone” have been used        interchangeably within this application. No difference or        distinction is meant, unless otherwise noted. One skilled in the        art will readily understand this.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

The invention also relates to base addition salts of the compounds ofthe invention. The chemical bases that may be used as reagents toprepare these pharmaceutically acceptable base salts are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

Suitable base salts are formed from bases which form non-toxic salts.Non-limiting examples of suitable base salts include the aluminum,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts. Hemisalts of acids and bases may also beformed, for example, hemisulphate and hemicalcium salts. For a review onsuitable salts, see Handbook of Pharmaceutical Salts: Properties,Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods formaking pharmaceutically acceptable salts of compounds of the inventionare known to one of skill in the art.

Certain of the compounds of the formula (I) may exist as geometricisomers. The compounds of the formula (I) may possess one or moreasymmetric centers, thus existing as two or more stereoisomeric forms.The present invention includes all the individual stereoisomers andgeometric isomers of the compounds of formula (I) and mixtures thereof.Individual enantiomers can be obtained by chiral separation or using therelevant enantiomer in the synthesis.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention. The compounds may also exist in one or morecrystalline states, i.e. polymorphs, or they may exist as amorphoussolids. All such forms are encompassed by the claims.

The invention also relates to prodrugs of the compounds of theinvention. Thus certain derivatives of compounds of the invention whichmay have little or no pharmacological activity themselves can, whenadministered into or onto the body, be converted into compounds of theinvention having the desired activity, for example, by hydrolyticcleavage. Such derivatives are referred to as “prodrugs”. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association).

This invention also encompasses compounds of the invention containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The present invention also includes isotopically-labeled compounds,which are identical to those recited in formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as, but not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe Schemes and/or in the Examples below, by substituting a readilyavailable isotopically-labeled reagent for a non-isotopically-labeledreagent.

All of the compounds of Formula I contain a sulfonyl moiety as depictedbelow:

This sulfonyl moiety will always be substituted with a lower alkylmoiety. Typically it will be methyl. The carbon atom adjacent to thesulfonyl may optionally be substituted, as represented by R². Typicallyboth R¹ and R² will be methyl.

As is readily apparent to one skilled in the art, the carbon adjacent tothe sulfonyl moiety is a chiral center. Therefore, the compounds canexist as the racemate, as the S-enantiomer, or as the R-enantiomer. In afurther embodiment, the compounds may be prepared and administered asthe R-enantiomer, as depicted below:

As is readily apparent to one skilled in the art, the compounds assynthesized will rarely be present exclusively as a single enantiomer.The opposite enantiomer (i.e the S-enantiomer) may be present in minoramounts (i.e. “substantially pure”). This minor amount can be up to 10w/w %, more typically no greater than 5 w/w %, in a further embodimentno greater than 1 w/w %, or more specifically, no greater than 0.5 w/w%.

All of the compounds of Formula I contain a pyridinone moiety asdepicted below:

This pyridinone ring will be connected to the rest of the molecule viathe 1- and 4-positions as depicted above. Position 3 will always besubstituted with a fluoro moiety as depicted above. The pyridinonemoiety may be optionally substituted, as depicted by the R³ moiety. R³may represent one non-hydrogen substituent, as defined above. Thisnon-hydrogen substituent may be located at either position 2 or 5 of thepyridinone ring. Typically R³ will represent hydrogen.

T will always be present in the molecule. It will be represented byethynyl, aryl or heteroaryl (either ring system may be substituted asdefined above.) Typically, T will be represented by phenyl, which may beoptionally substituted. When T is heteroaryl, it will be linked to thepyridinone via a carbon-carbon bond (i.e. the heteroatom(s) will not bebonded to the pyridinone). If E is present, and D represents a bond,then it may represent any chemically permissible bond, i.ecarbon-carbon, carbon-nitrogen, etc.

The presence of D and E are optional. If present, D will typically be abond and E will be represented by either a 5- to 6-membered heteroarylor a (C₃-C₆) cycloalkyl, either of which may be optionally substitutedas defined above.

More specific embodiments of the invention include compounds of FormulaI in which:

-   -   a) R¹ is methyl;    -   b) R² is methyl;    -   c) R³ is hydrogen;    -   d) the compound is present as the R-enantiomer (i.e.        substantially pure);    -   e) T is phenyl, which may be optionally substituted and D and E        are both absent; and    -   f) T is phenyl, D is a bond and E is either C₃-C₆ cycloalkyl or        a 5- to 6-membered heteroaryl, either of which may be optionally        substituted.

A further embodiment of the invention is directed to compounds ofFormula I, substantially pure in which:

-   -   a) R¹ and R² are each methyl, R³ is hydrogen, and T, D and E are        as defined;    -   b) R¹ and R² are each methyl, R³ is hydrogen, T is optionally        substituted phenyl and both E and D are absent;    -   c) R¹ and R² are each methyl, R³ is hydrogen, T is optionally        substituted phenyl, D is a bond and E is a 5- to 6-membered        heteroaryl, which may be optionally substituted; and    -   d) R¹ and R² are each methyl, R³ is hydrogen, T is optionally        substituted phenyl, D is a bond and E is C₃-C₆ cycloalkyl, which        may be optionally substituted.

In a further embodiment, the invention is directed to a subgenusrepresented by formula Ia below, in which the molecule is present as theR-enantiomer (i.e. the S-enantiomer may optionally be present in minoramounts). As depicted below, R¹ and R² are methyl, R³ is hydrogen, bothE and D are absent and T is substituted phenyl. More specifically R^(a)is represented by one or more substituents selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, fluorine, chlorine, hydroxy,trifluoromethyl and trifluoromethoxy.

In a further embodiment, the invention is directed to a subgenusrepresented by formula Ib below, in which the molecule is present as theR-enantiomer (i.e. the S-enantiomer may optionally be present as a minorimpurity). As depicted below, R¹ and R² are methyl, R³ is hydrogen, T isphenyl, D is a bond and E is a 5- to 6-membered heteroaryl, which may beoptionally substituted.

In a more specific embodiment of the invention, the LpxC inhibitor isthe following compound, or its pharmaceutically acceptable salt:

In a more specific embodiment of the invention, the LpxC inhibitor isthe following compound, or its pharmaceutically acceptable salt:

Synthesis

The compounds of Formula I can be prepared by a variety of methods thatare analogously known in the art. The reaction schemes presented belowillustrate two alternative methods for preparing these compounds.Others, including modifications thereof, will be readily apparent to oneskilled in the art.

The synthesis of the compounds of Formula I is depicted below in SchemeA. The first step is to carry out the N-alkylation depicted in Step A.The pyridinone of structure 1 is reacted with the sulfonyl derivative ofstructure 2 generating the intermediate of structure 3. Structure 3 canbe further derivatized to generate the compounds of Formula I. Twoalternative syntheses are depicted (Option A or B), but the reader willreadily note they are variations of the same synthesis. The onlydifference is the order in which the steps are carried out.

Initially in Option A, the halide, depicted by X, at the 4-position ofthe pyridinone of structure 3 is displaced by the desired terminalmoiety E-D-T-M¹, in which M¹ is a metal species, such as a boronderivative suitable for undergoing a typical cross-coupling such as aSuzuki-Miyaura reaction. Hydrolysis, or removal, of the ethyl protectinggroup (or other suitable protecting groups) in Step C affords thecompound of structure 5. The terminal carboxylic acid of structure 5 isthen converted to the protected hydroxamic acid derivative as depictedby structure 8. Deprotection of the protected hydroxamic acid derivativeof structure 8, as depicted in Step H, affords the final product ofFormula I. While these reactions are well known to one skilled in theart, they are discussed in greater detail below.

Initially, in Option B of Scheme A, the ethyl protecting group (or otherconventional protecting groups) is removed from the pyridinone ofstructure 3 generating the compound of structure 6 as depicted in StepE. In Step F, the terminal carboxylic acid of structure 6 is convertedto the protected hydroxamic acid derivative of structure 7 via amidationconditions. In Step G, the halide function at the 4-position on thepyridinone moiety is then directly displaced by the desired terminalmoiety, E-D-T-M¹, via a coupling reaction to afford the protectedhydroxamic acid derivatives of structure 8. As before, deprotection ofthe protected hydroxamic acid derivatives, as depicted in Step H,affords the compounds of Formula I.

The N-alkylation depicted above in Step A can be carried out usingtechniques well known to one skilled in the art. One of the startingmaterials is the 2-pyridinone derivative of structure 1. In thispyridinone, X will represented by a halide and R³ will be represented bythe same moiety as is desired in the final product. Many of thesepyridinone derivatives are known in the art and the remainder can beproduced using synthetic techniques analogously known in the art. Thereader's attention is directed to Tet. Lett. (2005) Vol 46, 7917, for adescription of such techniques. Preparation 2 infra, also illustratestheir preparation.

The other reactant in the N-alkylation depicted in Step A is theprotected alkyl sulfonate of structure 2, in which R¹ and R² arerepresented by the same moiety as is desired in the final product. Anethyl protecting group is portrayed, but any standard protecting groupmay be substituted. These alkyl sulfonates are also known in the art.The reader's attention is directed to Journal of Organic Chemistry,(1980) Vol 45, 8, 1486-1489 for a description of their preparation.Preparation 1 infra, also illustrates their preparation

The N-alkylation can be carried out as is known in the art. Typically,equivalent amounts of the compounds of structure 1 and 2 are contactedin a mixture of aprotic and protic solvents, such as tetrahydrofuran andt-butanol, in the presence of a base such as potassium carbonate, cesiumcarbonate, sodium carbonate, sodium hydride, etc. A transfer agent, suchas tetrabutyl ammonium bromide, can be utilized, if desired. Thereactants are typically heated and the reaction is allowed to proceed tocompletion. The desired product of structure 3 can be isolated bymethods known in the art. If desired, the product of structure 3 can bepurified, or alternatively the crude can be used in the next step of thereaction. Preparation 2 infra, illustrates such an N-alkylation.

Scheme A illustrates how to incorporate the hydroxamic acid moiety intothe molecules. Initially, the protecting group is removed from thecarboxylic acid, thereby generating the intermediate of structure 5 and6, as depicted in Step C (Option A) and Step E (Option B) respectively.The manner in which this is accomplished will vary with the identity ofthe actual protecting group and is well known to those skilled in theart. The reader's attention is directed to McOmie or Greene supra, for adiscussion of potential protecting groups and methods for their removal.Preparation 2 infra describes how to remove an ethyl moiety as depictedin Scheme A.

In Steps F and D, the hydroxamic acid moiety as depicted, isincorporated into the molecule. A protected hydroxylamine source may beused followed by a subsequent deprotection reaction (alternatively,hydroxylamine may be directly incorporated to eliminate the deprotectionsteps). In either case the hydroxamic acid is incorporated into themolecule using standard amidation reactions. For example, the compoundof structure 5 (Option A) or 6 (Option B) may be contacted with anexcess of oxalyl chloride, in an aprotic solvent such as dichloromethanefor a sufficient period of time to allow the formation of thecorresponding acid chloride, followed by the addition of an excess ofeither hydroxylamine or protected hydroxylamine. The reaction is thenallowed to proceed to completion and the protected intermediates ofstructure 7 (Option B) or 8 (Option A) is isolated from the reactionmedium and purified as is known in the art. As mentioned above, anydeprotection may be carried out as is known in the art (See Greene orMcOmie supra). Alternatively, the amide can be formed using the amidecoupling reagent, 1,1′-carbonyldiimidazole (CDI),2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), as is known in theart.

Scheme A also depicts how to incorporate the terminal moiety, E-D-T,into the molecule. Regardless of whether Option A or Option B is chosen,a coupling reaction is ultimately carried out to attach the terminalmoiety, E-D-T, to the 4-position of the pyridinone intermediate. InScheme A, the co-reactant is depicted as E-D-T-M¹, where E-D-T-M¹represents the same moiety as desired in the final product, except thatit will be substituted with a metal (or metalloid) such as magnesium,copper, boronic ester/acid, etc. at the desired point of attachment tothe pyridinone intermediate of structure 3 or 7 (i.e. the otherreactant). The terminal groups encompassed by Formula I, i.e E-D-T, areeither known in the art or can be prepared by methods analogously knownin the art.

The coupling reaction can be carried out by a variety of techniques. TheSuzuki-Miyaura strategy can be used to form the carbon-carbon bond. Insuch a reaction M¹ will be represented by a boronic acid/ester.Equivalent molar amounts of the reactants will be contacted in a solventsuch as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water,toluene, or a mixture thereof in the presence of a transition metalcatalyst such as a free or resin bound palladium or nickel species,together with a base such as sodium carbonate, potassium carbonate,cesium fluoride, cesium carbonate, etc. The reaction mixture can beheated by microwave or by other conventional techniques until adequateconversion is achieved. Once complete, the desired product may beisolated and recovered from the reaction and further purified as isknown in the art. Analogously, the Castro-Stevens orSonogashira-Hagihara strategy can be employed; the T moiety will be asuitable terminal acetylene species reacted in the presence of coppersalt such as copper iodide. In such a reaction M¹ can be represented bythe in situ generated cuprate species. Equivalent molar amounts of thereactants will be contacted in a solvent such as tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide or a mixture thereof in thepresence of a transition metal catalyst such as free or resin boundpalladium or nickel, together with an appropriate base such as asuitable organic base for example N,N-diisopropylethylamine. Thereaction mixture can be heated by microwave or by other conventionaltechniques until adequate conversion is achieved. Once complete, thedesired product may be isolated and recovered from the reaction andfurther purified as is known in the art.

The reaction schemes depicted above for producing the compound ofFormula I, are merely illustrative. As is readily apparent to oneskilled in the art, they may be modified depending upon the specificcompound, availability of reagents, etc.

Medical and Veterinary Uses

The compounds may be used for the treatment or prevention of infectiousdisorders, especially those caused by susceptible and multi-drugresistant (MDR) Gram-negative bacteria. Examples of such Gram-negativebacteria include Acinetobacter baumannii, Acinetobacter spp.,Achromobacter spp., Aeromonas spp., Bacteroides fragilis, Bordetellaspp., Borrelia spp., Brucella spp., Campylobacter spp., Citrobacterdiversus (koseri), Citrobacter freundii, Enterobacter aerogenes,Enterobacter cloacae, Escherichia coli, Francisella tularensis,Fusobacterium spp., Haemophilus influenzae (β-lactamase positive andnegative), Helicobacter pylori, Klebsiella oxytoca, Klebsiellapneumoniae (including those encoding extended-spectrum β-lactamases(hereinafter “ESBLs”), Legionella pneumophila, Moraxella catarrhalis(β-lactamase positive and negative), Morganella morganii, Neisseriagonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Porphyromonasspp., Prevotella spp., Mannheimia haemolyticus, Pasteurella spp.,Proteus mirabilis, Providencia spp., Pseudomonas aeruginosa, Pseudomonasspp., Salmonella spp., Shigella spp., Serratia marcescens, Treponemaspp., Burkholderia cepacia, Vibrio spp., Yersinia spp., andStenotrophomonas mulophilia. Examples of other gram negative organismsinclude members of the Enterobacteriaceae that express ESBLs; KPCs,CTX-M, metallo-β-lactamases (such as NDM-1, for example), and AmpC-typebeta-lactamases that confer resistance to currently availablecephalosporins, cephamycins, carbapenems, and beta-lactam/beta-lactamaseinhibitor combinations.

In a more specific embodiment, the Gram-negative bacteria are selectedfrom the group consisting of Acinetobacter baumannii, Acinetobacterspp., Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae,Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratiamarcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa andmembers of the Enterobacteriaceae and Pseudomonas that express ESBLs,KPCs, CTX-M, metallo-β-lactamases, and AmpC-type beta-lactamases thatconfer resistance to currently available cephalosporins, cephamycins,carbapenems, and beta-lactam/beta-lactamase inhibitor combinations.

Examples of infections that may be treated with the compounds of FormulaI include nosocomial pneumonia, urinary tract infections, systemicinfections (bacteremia and sepsis), skin and soft tissue infections,surgical infections, intraabdominal infections, lung infections inpatients with cystic fibrosis, patients suffering from lung infections,endocarditis, diabetic foot infections, osteomyelitis, and centralnervous system infections.

In addition, the compounds can be used to treat Helicobacter pyloriinfections in the GI tract of humans (and other mammals). Elimination ofthese bacteria is associated with improved health outcomes includingfewer dyspeptic symptoms, reduced peptic ulcer recurrence andrebleeding, reduced risk of gastric cancer, etc. A more detaileddiscussion of eradicating H. pylori and its impact on gastrointestinalillness may be found at: on the world-wide web at informahealthcare.com;and Expert Opin. Drug Saf. (2008) 7(3).

In order to exhibit this anti-infective activity, the compounds need tobe administered in a therapeutically effective amount. A“therapeutically effective amount” is meant to describe a sufficientquantity of the compound to treat the infection, at a reasonablebenefit/risk ratio applicable to any such medical treatment. It will beunderstood, however, that the attending physician, within the scope ofsound medical judgment, will decide the total daily dosage of thecompound. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. As a general guidelinehowever, the total daily dose will typically range from about 0.1mg/kg/day to about 5000 mg/kg/day in single or in divided doses.Typically, dosages for humans will range from about 10 mg to about 3000mg per day, in a single or multiple doses.

Any route typically used to treat infectious illnesses, including oral,parenteral, topical, rectal, transmucosal, and intestinal, can be usedto administer the compounds. Parenteral administrations includeinjections to generate a systemic effect or injections directly into tothe afflicted area. Examples of parenteral administrations aresubcutaneous, intravenous, intramuscular, intradermal, intrathecal, andintraocular, intranasal, intravetricular injections or infusionstechniques. Topical administrations include the treatment of areasreadily accessible by local application, such as, for example, eyes,ears including external and middle ear infections, vaginal, open wound,skin including the surface skin and the underneath dermal structures, orlower intestinal tract. Transmucosal administration includes nasalaerosol or inhalation applications.

Formulations

Compounds of the invention can be formulated for administration in anyway for use in human or veterinary medicine, by analogy with otherbioactive agents such as antibiotics. Such methods are known in the artand are summarized below.

The composition can be formulated for administration by any route knownin the art, such as subdermal, by-inhalation, oral, topical orparenteral. The compositions may be in any form known in the art,including but not limited to tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention can be presented as,for instance, ointments, creams or lotions, ophthalmic ointments/dropsand otic drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients, etc. Such topical formulationsmay also contain conventional carriers, such as cream or ointment basesand ethanol or oleyl alcohol for lotions. Such carriers may be present,for example, from about 1% up to about 98% of the formulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate, talc, polyethylene glycol or silica;disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulphate. The tablets may be coated according tomethods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerin, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being typical. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle or other suitable solvent. Inpreparing solutions, the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, agents such as a local anesthetic,preservative and buffering agents can be dissolved in the vehicle. Toenhance the stability, the composition can be frozen after filling intothe vial and the water removed under vacuum. The dry lyophilized powderis then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The compositions may contain, for example, from about 0.1% by weight, toabout 100% by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill contain, for example, from about 0.5-1000 mg of the activeingredient. The dosage as employed for adult human treatment will range,for example, from about 10 to 3000 mg per day, depending on the routeand frequency of administration.

If desired, the compounds of the invention may be administered incombination with one or more additional antibacterial agents (“theadditional active agent”). Such use of compounds of the invention incombination with an additional active agent may be for simultaneous,separate or sequential use.

The Examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing Examples and preparations. In the following Examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES Experimental Procedures

Experiments were generally carried out under an inert atmosphere(nitrogen or argon), particularly in cases where oxygen-ormoisture-sensitive reagents or intermediates were employed. Commercialsolvents and reagents were generally used without further purification,including anhydrous solvents where appropriate (generally Sure-Seal™products from the Aldrich Chemical Company, Milwaukee, Wis.). Massspectrometry data is reported from either liquid chromatography-massspectrometry (LCMS) or atmospheric pressure chemical ionization (APCI).Chemical shifts for nuclear magnetic resonance (NMR) data are expressedin parts per million (ppm, δ) referenced to residual peaks from thedeuterated solvents employed. Melting points are uncorrected. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard5989®, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C.

For syntheses referencing procedures in other Examples, reactionconditions (length of reaction and temperature) may vary. In general,reactions were followed by thin layer chromatography or massspectrometry, and subjected to work-up when appropriate. Purificationsmay vary between experiments: in general, solvents and the solventratios used for eluents/gradients were chosen to provide appropriateR_(f)s or retention times.

In the discussion above and in the Examples below, the followingabbreviations have the following meanings. If an abbreviation is notdefined, it has its generally accepted meaning.

-   -   Ac=acetate    -   ACN=acetonitrile    -   AC₂O=acetic anhydride    -   APCl=atmospheric pressure chemical ionization    -   Aq.=aqueous    -   9-BBN=9-Borabicyclo[3.3.1]nonane    -   bd=broad doublet    -   bm=broad multiplet    -   bs=broad singlet    -   BOC=tert-butoxycarbonyl    -   ° C.=degrees celsius    -   CBZ=benzyloxycarbonyl    -   CDI=1,1′-carbonyldiimidazole    -   CDMT=2-chloro-4,6-dimethoxy-1,3,5-triazine    -   CM=centimeter    -   d=doublet    -   DCC=1,3-dicyclohexylcarbodiimide    -   DCM=dichloromethane    -   dd=doublet of doublets    -   ddd=doublet of doublets of doublets    -   DIAD=diisopropyl azodicarboxylate    -   DME=dimethyl ether    -   DMF=dimethylformamide    -   DMA=dimethylacetamide    -   DMAP=4-dimethylaminopyridine    -   DMSO=dimethyl sulfoxide    -   dq=doublet of quartets    -   dt=doublet of triplets    -   EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   eq.=equivalents    -   EtO=ethoxy    -   Et₂O=diethyl ether    -   EtOAc=ethyl acetate    -   g=grams    -   GCMS=gas chromatography mass spectromety    -   h=hours    -   ¹H=proton    -   HATU=(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate)    -   HCl=hydrochloric acid    -   H₂N-OTHP=O-tetrahydro-2H-pyran-2-yl-hydroxylamine    -   HOBT=Hydroxybenzotriazole    -   HPLC=high pressure liquid chromatography    -   Hz=hertz    -   IPA=isopropanol    -   J=coupling constant    -   KOAc=potassium acetate    -   K₃PO₄=potassium phosphate    -   L=liter    -   LCMS=liquid chromatography mass spectrometry    -   LDA=lithium diisopropylamide    -   LG=leaving group    -   LiHMDS=lithium hexamethyldisilazide/lithium        bis(trimethylsilyl)amide    -   m=multiplet    -   M=molar    -   M %=mole percent    -   max=maximum    -   mCPBA=meta-chloroperbenzoic acid    -   MeOH=methanol    -   meq=milliequivalent    -   MeTHF=2-methyltetrahydrofuran    -   mg=milligram    -   MgSO₄=magnesium sulfate    -   MHz=megahertz    -   min=minutes    -   mL=milliliter    -   mm=millimeter    -   mmol=millimole    -   MS=mass spectrometry    -   MTBE=methyl tert-butyl ether    -   m/z=mass to charge ratio    -   N=normality    -   NaHCO₃=sodium bicarbonate    -   Na₂SO₄=sodium sulfate    -   NH₄Cl=ammonium chloride    -   NMM=N-methylmorpholine    -   NMP=1-methyl-2-pyrrolidinone    -   NMR=nuclear magnetic resonance    -   Pd=palladium    -   Pd EnCat™=palladium acetate and BINAP, microencapsulated in        polyurea matrix 0.39 mmol/g Pd loading BINAP 0.25, Pd 1.0    -   Pd(dppf)Cl₂=bis(diphenylphosphino)ferrocenepalladium(II)        chloride Pd(dppf)Cl₂ dichloromethane complex    -   Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)    -   ppt=precipitate    -   p-TLC=preparative thin layer chromatography    -   PyBop=benzotriazole-1-yl-oxy-trispyrrolidinophosphonium        hexafluorophosphate    -   q=quartet    -   R_(f)=retention factor    -   rt=room temperature    -   s=singlet    -   sat.=saturated    -   t or tr=triplet    -   TBAB=tetrabutylammoinum bromide    -   TBS=tert-butyldimethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   THP=tetrahyropyranyl    -   TLC=thin layer chromatography    -   TMS=trimethylsilyl    -   TPP=triphenylphosphine    -   TPPO=triphenylphosphine oxide    -   μL=microliter

Preparation of Starting Materials Preparation 1 Synthesis of Template 1(T1): Ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate and IndividualEnantiomers (R) and (S)

Step A) Ethyl 2-(methylsulfonyl)propanoate

Sodium methanesulfinate (103 g, 937 mmol) was combined with ethyl2-chloropropionate (109 g, 892 mmol) in ethanol (350 mL) in a 500 mL oneneck round bottom flask. The reaction was heated to 77° C. for 20 h, andthen allowed to cool to room temperature. The solids were removed byfiltration through celite, and the filter pad was washed with ethanol.The combined filtrates were concentrated in vacuo. The crude product wassuspended in diethyl ether (250 mL), and solids were removed byfiltration. The filtrate was concentrated in vacuo to afford the titlecompound as a pale yellow oil (51 g, 73%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.32 (t, J=7.05 Hz, 3 H) 1.67 (d, J=7.47 Hz, 3 H)3.05 (s, 3 H) 3.83-3.92 (m, 1 H) 4.18-4.37 (m, 2 H).

Step B) Ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate

Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) waswashed with hexanes (2×10 mL) in a 100 mL two neck round bottom flaskunder nitrogen then suspended in DMF (30 mL). The suspension was treateddropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) inDMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., andtreated drop-wise with 1,2-dibromoethane (5.17 mL, 58.8). The mixturewas allowed to warm to room temperature while stirring overnight. Themixture was quenched with saturated aq ammonium chloride (100 mL) andextracted with diethyl ether (4×50 mL). Combined organics were washedwith 50% saturated sodium chloride (4×50 mL), dried (MgSO₄), andconcentrated in vacuo. Crude material was purified via silicachromatography (350 g, 230-400 mesh) and an eluent of EtOAc in hexanes(10-20%) to afford the title compound as a pale yellow oil (7.9 g, 50%).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3 H) 1.64 (s, 3H) 2.49-2.59 (m, 1 H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1 H) 3.05 (s,3 H) 3.33-3.41 (m, 1 H) 3.46-3.54 (m, 1 H) 4.22-4.37 (m, 2 H).

Step C) Chiral Separation of Ethyl4-bromo-2-methyl-2-(methylsulfonyl)butanoate

Crude ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.82 kg) waspurified via flash chromatography using an LP-600 column and toluene asthe eluent to afford pure ethyl4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.63 kg). The purifiedmaterial was dissolved in ethanol (75 g/L) and resolved via chiralcolumn chromatography (conditions listed in Table 1) on MCC-2 to affordenantiomer #1 (738.4 g, rt=4.719 min, [α]₅₈₉ ²⁰=+14.1° at 99% ee andenantiomer #2 (763.8 g, rt=4.040 min) at 95% ee. Purity of theenantiomers was determined via chiral HPLC, 4.6×250 mm Chiralpak AD, 10μcolumn, 215 nm wavelength, mobile phase: ethanol, isocratic elution at 1mL/min at ambient temperature.

TABLE 1 Stationary Phase ChiralPak AD, 20μ Column Dimension/Temp 5 × 10cm/30° C. Mobile Phase 100% ethanol Feed Concentration 75 g/L in mobilephase Feed Rate 4.0 mL/min Eluent Rate 90.5 mL/min Raffinate Rate 35.6mL/min Extract Rate 58.9 mL/min Recycling Rate 262 mL/min Period Time1.0 min Enantiomer #1 was determined to be ethyl(2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, Template 1 (T1).

Preparation 2

Scheme B illustrates the preparation of ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(T2) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(T3) and the corresponding racemic and diastereomeric mixtures ethyl4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(T4) and4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(T5).

Synthesis of Template 3 (T3):(2R)-4-(5-Fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Step A) Compound III: 5-Fluoro-4-iodopyridin-2(1H)-one

Concentrated HCl (50 mL) was added to a mixture of2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL)and water (100 mL). The mixture was heated to reflux and stirred at thistemperature overnight. The reaction was concentrated to dryness and theresidue was triturated in water (20 mL). The solids were collected viafiltration and washed with water (2×30 mL) and hexanes (3×30 mL). Thesolid was dried under vacuum to afford the title compound as a yellowsolid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.68 (d, J=2.34 Hz, 1 H) 11.50 (br. s., 1H).

Step B) Template 2 (T2): Ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

Cesium carbonate (1.77 g, 5.44 mmol) was added to a suspension of5-fluoro-4-iodopyridin-2(1H)-one (1.00 g, 4.2 mmol) and ethyl(2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.56 g, 5.44 mmol) inanhydrous THF (45 mL). The reaction was heated to 70° C. and stirred atthis temperature overnight. The reaction was quenched with water (100mL) and extracted with EtOAc (2×100 mL). The combined organics werewashed with brine (100 mL), dried (MgSO₄), filtered, and concentrated.The crude product was purified via flash chromatography using a VarianSF15-24 g column and an eluent of EtOAc in n-heptane (30-80%) to affordthe title compound as a yellow residue (691 mg, 37%). MS (LCMS) m/z446.0 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, 3 H) 1.75 (s,3 H) 2.37-2.57 (m, 2 H) 3.10 (s, 3 H) 3.83-4.02 (m, 1 H) 4.16-4.37 (m, 3H) 7.15 (d, 1 H) 7.20 (d, J=3.32 Hz, 1 H).

Step C) Compound IV:(2R)-4-(5-Fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid

Potassium hydroxide (669 mg, 7.7 mmol) was added to a solution of ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(691 mg, 1.55 mmol) in 2-methyltetrahydrofuran:water (2:1 22.5 mL) andthe solution was stirred at 70° C. for 2 h. The reaction was dilutedwith 1 N aq NaOH (50 mL). The organics were separated and the aqueouslayer was washed with EtOAc (2×50 mL), and acidified to a pH of 3 using3 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×60 mL),dried (MgSO₄), filtered and concentrated to afford a yellow-white solid(290 mg, 44.8%). MS (LCMS) m/z 418.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.53 (s, 3 H) 2.08-2.20 (m, 1 H) 2.36-2.48 (m, 1 H) 3.13 (s, 3 H)3.79-4.02 (m, 2 H) 7.03 (d, J=6.05 Hz, 1 H) 7.96 (d, J=4.29 Hz, 1 H)13.82 (br. s., 1 H).

Step D) Template 3 (T3):(2R)-4-(5-Fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N-Methylmorpholine (120 uL, 1.1 mmol) was added to a solution of CDMT(178 mg, 1.01 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid (280 mg, 0.762 mmol) in 2-methyltetrahydrofuran (7.60 mL) and thereaction was stirred at rt for 1 h. THP-hydroxylamine (117 mg, 1.00mmol) was added to the reaction and the reaction was stirred overnightat rt. The reaction was quenched with water (50 mL) and the aqueouslayer was extracted with EtOAc (3×50 mL). The combined organics werewashed with brine (50 mL), dried (MgSO₄), filtered, and concentrated toafford the title compound as an off-white solid (399.8 mg) MS (LCMS)515.0 (M−1).

Example 1(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Step A)2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole

Pd(dppf)Cl₂ (70.2 mg, 0.10 mmol) was added to a suspension of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (291 mg, 1.15mmol), 2-(4-bromophenyl)-2H -tetrazole (215 mg, 0.96 mmol), andpotassium acetate (191 mg, 1.91 mmol) in 1,4-dioxane (4.78 mL). Theresulting suspension was heated to 80° C. and stirred at thistemperature overnight. The reaction was allowed to cool, filteredthrough celite, and concentrated in vacuo. The crude product waspurified via flash chromatography using a 40 g silica gel Redisep columnand an eluent of EtOAc in n-heptane (0-50%) to afford the title compoundas a light yellow solid (258 mg, 99%). MS (LCMS) m/z 273.2 (M+1). ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12 H) 7.66-7.73 (m, 2 H)7.96-8.02 (m, 2 H) 9.01 (s, 1 H).

Step B)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Pd EnCat™ (317 mg, 0.10 mmol) was added to a mixture of potassiumcarbonate (393 mg, 2.84 mmol),2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole(258.4 mg, 0.95 mmol), and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(490 mg, 0.95 mmol), T3, in 1,4-dioxane:water (4:1, 10 mL). The reactionwas heated to 80° C. and stirred at this temperature overnight. Thereaction was filtered through celite, and the filter pad was washed withmethanol (250 mL). The combined filtrates were concentrated underreduced pressure, and the resulting crude material was purified viaflash chromatography using an eluent of EtOAc in n-heptane (20-100%) andmethanol in EtOAc (0-10%) to afford the title compound as a light tansolid (500 mg, 98%). MS (LCMS) m/z 534.4 (M−1). 0

Step C)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added toa solution of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(500 mg, 0.94 mmol) in dichloromethane:methanol (5:1, 6 mL) at roomtemperature. The reaction was stirred for 1 h then was concentratedunder reduced pressure affording a residue, which was triturated indiethyl ether:pentane (1:1) overnight. The solid was collected viafiltration and dried under reduced pressure to afford the title compoundas a solid (340 mg, 76%). MS (LCMS) m/z 451.0 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.56 (s, 3 H) 2.09-2.21 (m, 1 H) 2.42-2.45 (m, 1 H) 3.09(s, 3 H) 3.78 (m, J=11.80, 11.80, 5.20 Hz, 1 H) 3.97-4.10 (m, 1 H) 6.63(d, J=7.61 Hz, 1 H) 7.84 (dd, J=8.68, 1.66 Hz, 2 H) 8.00-8.15 (m, 3 H)10.16 (s, 1 H) 11.08 (br. s., 1 H).

Example 2 2R)-4-[5-Fluoro-4-(2-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(2-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (470 mg, 48.7%) was obtained as a solid from(2-fluoro-3-methylphenyl)boronic acid (388 mg, 2.52 mmol) using aprocedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 499 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.49-1.57 (m, 3 H) 1.59 (d, J=3.71 Hz, 3 H) 1.64-1.74(m, 3 H) 2.16-2.26 (m, 1 H) 2.27-2.31 (m, 3 H) 3.10 (d, J=5.66 Hz, 3 H)3.31 (s, 1 H) 3.47-3.55 (m, 1 H) 3.72-3.88 (m, 1 H) 3.90 (s, 1 H)3.99-4.15 (m, 2 H) 4.94-4.99 (m, 1 H) 6.47 (d, J=7.22 Hz, 1 H) 7.20-7.26(m, 1 H) 7.26-7.32 (m, 1 H) 7.40-7.47 (m, 1 H) 8.01 (dd, J=11.90, 5.85Hz, 1 H) 11.52 (d, J=3.51 Hz, 1 H).

Step B)(2R)-4-[5-Fluoro-4-(2-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (185 mg, 46.6%) was obtained as a solid from(2R)-4-[5-fluoro-4-(2-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(477 mg, 0.957 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 415 (M+1) ¹H NMR (400 MHz, DMSO-d₆) δppm 1.54 (s, 3 H) 2.13 (ddd, J=13.03, 11.07, 4.78 Hz, 1 H) 2.40-2.45 (m,1 H) 3.08 (s, 3 H) 3.76 (td, J=11.81, 5.07 Hz, 1 H) 4.02 (td, J=11.85,5.17 Hz, 1 H) 6.53 (d, J=7.61 Hz, 1 H) 7.45-7.64 (m, 4 H) 8.02 (d,J=6.63 Hz, 1 H) 9.11-9.26 (m, 1 H) 11.00-11.13 (m, 1 H).

Example 3 (2R)-4-[4-(4-Chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(4-Chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (870 mg, 59.8%) was obtained as a solid from(4-chlorophenyl)boronic acid (610 mg, 4.36 mmol) using a procedureanalogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 502 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.17-1.28 (m, 2 H) 1.45-1.53 (m, 3 H) 1.56 (d, J=3.71 Hz, 3 H)1.60-1.72 (m, 3 H) 2.08-2.23 (m, 1 H) 3.07 (d, J=6.44 Hz, 3 H) 3.48 (d,J=11.12 Hz, 1 H) 3.67-3.85 (m, 1 H) 3.96-4.12 (m, 2 H) 4.88-4.97 (m, 1H) 6.53 (d, J=7.61 Hz, 1 H) 7.50-7.62 (m, 3 H) 8.00 (dd, J=13.07, 6.63Hz, 1 H) 11.50 (s, 1 H).

Step B)(2R)-4-[4-(4-Chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (340 mg, 47.0%) was obtained as a solid from(2R)-4-[4-(4-chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(870 mg, 1.74 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 417 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.54 (s, 3 H) 2.13 (ddd, J=13.12, 11.27, 5.07 Hz, 1 H) 2.37-2.45 (m,1 H) 3.08 (s, 3 H) 3.76 (td, J=11.90, 5.07 Hz, 1 H) 3.93-4.12 (m, 1 H)6.53 (d, J=7.61 Hz, 1 H) 7.49-7.66 (m, 4 H) 8.02 (d, J=6.63 Hz, 1 H)9.21 (s, 1 H) 10.95-11.17 (m, 1 H).

Example 4(2R)-4-[5-Fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (230 mg, 81.7%) was obtained as a solid from(2-fluorophenyl)boronic acid (122 mg, 0.871 mmol) using a procedureanalogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 485 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.21-1.28 (m, 2 H) 1.48-1.56 (m, 3 H) 1.58 (d, J=3.71 Hz, 3 H)1.63-1.74 (m, 3 H) 2.15-2.26 (m, 1 H) 3.10 (d, J=5.66 Hz, 3 H) 3.34 (br.s., 1 H) 3.51 (d, J=10.73 Hz, 1 H) 3.71-3.88 (m, 1 H) 3.99-4.15 (m, 2 H)4.94-4.99 (m, 1 H) 6.50 (d, J=7.02 Hz, 1 H) 7.31-7.40 (m, 2 H) 7.46-7.53(m, 1 H) 7.56 (m, J=7.76, 7.76, 5.56, 1.76 Hz, 1 H) 8.01 (dd, J=11.90,5.85 Hz, 1 H) 11.51 (d, J=3.32 Hz, 1 H).

Step B)(2R)-4-[5-Fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (68 mg, 36.0%) was obtained as a solid from(2R)-4-[5-fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(230 mg, 0.475 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 401 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.58 (s, 3 H) 2.18 (td, J=12.15, 4.98 Hz, 1 H) 2.47 (m, 1 H) 3.12(s, 3 H) 3.79 (td, J=11.85, 5.17 Hz, 1 H) 4.07 (td, J=11.81, 4.68 Hz, 1H) 6.50 (d, J=7.02 Hz, 1 H) 7.30-7.44 (m, 2 H) 7.46-7.64 (m, 2 H) 8.04(d, J=6.05 Hz, 1 H) 9.20-9.32 (m, 1 H) 10.99-11.17 (m, 1 H).

Example 5(2R)-4-[4-(2,3-Dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(2,3-Dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (198 mg, 61.0%) was obtained as a solid from2,3-dihydro-1-benzofuran-5-ylboronic acid (153 mg, 0.871 mmol) using aprocedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 509 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.46-1.56 (m, 2 H) 1.58 (d, J=4.10 Hz, 3 H) 1.63-1.76 (m, 3 H)2.12-2.27 (m, 1 H) 2.40-2.48 (m, 1 H) 3.10 (d, J=6.05 Hz, 3 H) 3.23 (t,J=8.78 Hz, 2 H) 3.35 (br. s, 1 H) 3.51 (d, J=12.10 Hz, 1 H) 3.67-3.88(m, 1 H) 3.98-4.15 (m, 2 H) 4.59 (t, J=8.78 Hz, 2 H) 4.96 (d, J=2.73 Hz,1 H) 6.46 (d, J=7.81 Hz, 1 H) 6.81-6.92 (m, 1 H) 7.28-7.39 (m, 1 H) 7.47(s, 1 H) 7.96 (dd, J=12.78, 6.73 Hz, 1 H) 11.55 (s, 1 H).

Step B)(2R)-4-[4-(2,3-Dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (165 mg, 53.0%) was obtained as a solid from(2R)-4-[4-(2,3-dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (198 mg, 0.389 mmol) using aprocedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 425 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.57 (s, 3 H) 2.16 (dd, J=5.56, 1.07 Hz, 1 H) 2.36-2.49 (m, 1 H)3.11 (s, 3 H) 3.23 (t, J=8.59 Hz, 2 H) 3.66-3.86 (m, 1 H) 4.04 (dd,J=6.15, 0.88 Hz, 1 H) 4.59 (t, J=8.78 Hz, 2 H) 6.45 (d, J=7.81 Hz, 1 H)6.87 (d, J=8.39 Hz, 1 H) 7.34 (dd, J=8.20, 1.95 Hz, 1 H) 7.46 (s, 1 H)7.98 (d, J=6.83 Hz, 1 H) 9.15-9.31 (m, 1 H) 11.01-11.19 (m, 1 H).

Example 6(2R)-4-[4-(3,4-Difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(3,4-Difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (760 mg, 52.1%) was obtained as a solid from(3,4-difluorophenyl)boronic acid (596 mg, 3.78 mmol) using a procedureanalogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 503 (M+1).

Step B)(2R)-4-[4-(3,4-Difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (350 mg, 55.0%) was obtained as a solid from(2R)-4-[4-(3,4-difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(760 mg, 1.51 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 419 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.57 (s, 3 H) 2.06-2.25 (m, 1 H) 2.38-2.48 (m, 1 H) 3.11 (s, 3 H)3.68-3.87 (m, 1 H) 3.96-4.18 (m, 1 H) 6.60 (d, J=7.61 Hz, 1 H) 7.37-7.52(m, 1 H) 7.52-7.65 (m, 1 H) 7.65-7.84 (m, 1 H) 8.06 (d, J=6.63 Hz, 1 H)9.13-9.39 (m, 1 H) 11.08 (s, 1 H).

Example 7(2R)-4-{5-Fluoro-2-oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (860 mg, 78.6%) was obtained as a solid from[4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (554 mg, 2.52 mmol) usinga procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 565 (M+1).

Step B)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (310 mg, 42.3%) was obtained as a solid from(2R)-4-{5-fluoro-2-oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(860 mg, 1.52 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 419 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.54 (s, 3 H) 2.06-2.22 (m, 1 H) 2.37-2.45 (m, 1 H) 3.08 (s, 3 H)3.74 (td, J=11.76, 4.98 Hz, 1 H) 3.93-4.10 (m, 1 H) 4.81 (q, J=8.98 Hz,2 H) 6.49 (d, J=7.61 Hz, 1 H) 7.16 (d, J=8.98 Hz, 2 H) 7.49-7.62 (m, 2H) 7.98 (d, J=6.63 Hz, 1 H) 9.21 (br. s., 1 H) 11.07 (s,

Example 8(2R)-4-[4-(3,4-Dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(3,4-Dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (500 mg, 82.3%) was obtained as a solid from3,4-dihydro-2H-chromen-6-ylboronic acid (228 mg, 1.28 mmol) using aprocedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 523 (M+1).

Step B)(2R)-4-[4-(3,4-Dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (240 mg, 57.1%) was obtained as a solid from(2R)-4-[4-(3,4-dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(500 mg, 0.957 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 1, Step C. MS (LCMS) m/z 439 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.52 (s, 3 H) 1.83-1.97 (m, 2 H) 2.12 (ddd, J=13.03, 11.27, 5.17 Hz,1 H) 2.34-2.44 (m, 1 H) 2.75 (t, J=6.34 Hz, 2 H) 3.07 (s, 3 H) 3.71 (td,J=11.76, 5.17 Hz, 1 H) 3.92-4.07 (m, 1 H) 4.08-4.20 (m, 2 H) 6.42 (d,J=7.61 Hz, 1 H) 6.79 (d, J=8.39 Hz, 1 H) 7.20-7.32 (m, 2 H) 7.94 (d,J=6.83 Hz, 1 H) 9.20 (br. s., 1 H) 11.07 (s, 1 H).

Example 9(2R)-4-{5-Fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) Ethyl(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate

1,4-Dioxane (10 ml) and 3 M aq K₃PO₄ (1.12 mL, 3.3 mmol) was added to aflask containing [4-(methylthio)phenyl]boronic acid (0.283 g, 1.68mmol), Pd(dppf)Cl₂ (82 mg, 0.112 mmol) and ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2, (500 mg, 1.12 mmol) that was previously flushed with nitrogen. Themixture was heated to 60° C. and stirred at this temperature for 1 h.The reaction mixture was diluted with EtOAc and washed with water. Theorganics were dried (MgSO₄), filtered, and concentrated. The crudeproduct was purified via flash chromatography on a 40 g silica columnand an eluent of EtOAc in n-heptane (0-100%) to afford the titlecompound as a gum (492 mg, 99%). MS (LCMS) m/z 442.1 (M+1). ¹H NMR (400MHz, CHLOROFORM-d)δ ppm 1.17-1.27 (m, 3 H) 1.74 (s, 3 H) 2.38-2.61 (m, 5H) 3.09 (s, 3 H) 3.88-4.02 (m, 1 H) 4.17-4.32 (m, 3 H) 6.57 (d, J=7.61Hz, 1 H) 7.21-7.34 (m, 3 H) 7.37-7.48 (m, 2 H).

Step B)(2R)-4-{5-Fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid

Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to asolution of ethyl(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate(0.492 g, 1.12 mmol) in THF:water (1:1, 14 mL) and the reaction wasallowed to stir at rt for 18 h. The reaction mixture was acidified using4 M aq HCl to afford a precipitate. The solid was collected viafiltration and dried under vacuum to afford the title compound as asolid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). ¹H NMR (400 MHz,DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.17 (ddd, J=13.42, 10.00, 5.07 Hz, 1 H)2.41-2.45 (m, 1 H) 2.49 (s, 3 H), 3.14 (s, 3 H) 3.78-4.15 (m, 2 H) 6.46(d, J=7.81 Hz, 1 H) 7.28-7.39 (m, 2 H) 7.43-7.55 (m, 2 H) 8.01 (d,J=6.83 Hz, 1 H).

Step C)(2R)-4-{5-Fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N,N-Diisopropylethylamine (450 uL, 2.45 mmol),O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (192 mg, 1.64 mmol) and HATU(447 mg, 1.23 mmol) were added to a solution of(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid (339 mg, 0.82 mmol) in DMF (10 mL). The reaction was allowed tostir at rt for 18 h. The reaction mixture was diluted with EtOAc andwashed with brine. The organics were dried (MgSO₄), filtered andconcentrated. The crude residue was purified via flash chromatographyusing a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%)to afford the title compound (420 mg, 100%). MS (LCMS) m/z 511.4 (M−1).

Step D)(2R)-4-{5-Fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Aqueous HCl (4 M, 3 mL) was added to a solution of2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(437 mg, 0.852 mmol) in THF (10 mL) and the reaction was allowed to stirat rt for 3 h. The reaction mixture was concentrated and then azeotropedwith EtOAc and n-heptane several times to give the title compound as anoff-white solid (233 mg, 64%). MS (LCMS) m/z 429.1 (M+1). ¹H NMR (400MHz, METHANOL-d₄) δ ppm 1.69 (s, 3 H) 2.37 (ddd, J=13.51, 10.59, 5.17Hz, 1 H) 2.51 (s, 3 H) 2.57-2.74 (m, 1 H) 2.82 (s, 3 H) 3.09 (s, 3 H)3.97 (ddd, J=13.12, 10.59, 5.56 Hz, 1 H) 4.27 (ddd, J=13.03, 10.49, 5.17Hz, 1 H) 6.68 (d, J=7.22 Hz, 1 H) 7.25-7.40 (m, 2 H) 7.47-7.59 (m, 2 H)7.90 (d, J=6.05 Hz, 1 H).

Example 10(2R)-4-[4-(4-Ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) Ethyl(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate

The title compound (320 mg, 64%) was obtained as a gum from(4-ethoxyphenyl)boronic acid (280 mg, 1.68 mmol) using a procedureanalogous to that described for ethyl(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate,Example 9, Step A. MS (LCMS) m/z 440.3 (M+1). ¹H NMR (400 MHz,CHLOROFORM-d)δ ppm 1.22 (t, J=7.12 Hz, 3 H) 1.40 (t, J=7.02 Hz, 3 H)1.73 (s, 3 H) 2.36-2.61 (m, 2 H) 3.09 (s, 3 H) 3.85-3.98 (m, 1 H) 4.07(dd, J=14.93, 7.12 Hz, 2 H) 4.25 (m, 3 H) 6.51-6.58 (m, 1 H) 6.93 (d,J=8.98 Hz, 3 H) 7.22-7.31 (m, 1 H) 7.44 (d, J=7.02 Hz, 1 H).

Step B)(2R)-4-[4-(4-Ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate(320 mg, 0.728 mmol) in tetrahydrofuran:water (1:1, 20 mL) and thereaction was allowed to stir at rt until complete. The reaction mixturewas acidified with 4 M aq HCl and extracted with EtOAc. The combinedorganic layers were dried (MgSO₄), filtered and concentrated to affordthe title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26-1.40 (m, 3 H) 1.54 (s, 3 H)2.07-2.26 (m, 1 H) 2.43 (d, J=6.24 Hz, 1 H) 3.14 (s, 3 H) 3.83-4.15 (m,4 H) 6.42 (d, J=7.81 Hz, 1 H) 6.93-7.07 (m, 2 H) 7.50 (dd, J=8.68, 1.85Hz, 2 H) 7.97 (d, J=6.83 Hz, 1 H).

Step C)(2R)-4-[4-(4-Ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (273 mg, 100%) was obtained from(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (220 mg, 0.535 mmol) using a procedure analogous to that describedfor(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 9, Step C. MS (LCMS) m/z 509.4 (M+1).

Step D)(2R)-4-[4-(4-Ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (205 mg, 83%) was obtained as a solid from(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(297 mg, 0.582 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 9, Step D. MS (LCMS) m/z 427.2 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.40 (t, J=6.93 Hz, 3 H) 1.69 (s, 3 H) 2.28-2.42 (m,1 H) 2.54-2.69 (m, 1 H) 3.09 (s, 3 H) 3.86-3.99 (m, 1 H) 4.09 (q, J=7.02Hz, 2 H) 4.18-4.32 (m, 1 H) 6.60 (d, J=7.42 Hz, 1 H) 7.01 (d, J=8.98 Hz,2 H) 7.54 (dd, J=8.78, 1.56 Hz, 2 H) 7.82 (d, J=6.24 Hz, 1 H).

Example 11(2R)-4-[5-Fluoro-2-oxo-4-(4-propylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-2-oxo-4-(4-propylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (75.5 mg, 21%) was obtained as a solid from(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (360 mg, 0.697 mmol) and (4-propylphenyl)boronic acid (171 mg, 1.04mmol) using a procedure analogous to that described for ethyl(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate,Example 9, Step A. MS (LCMS) m/z 507.4 (M−1).

Step B)(2R)-4-[5-Fluoro-2-oxo-4-(4-propylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (58 mg, 94%) was obtained as a solid from(2R)-4-[5-fluoro-2-oxo-4-(4-propylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(75 mg, 0.15 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 9, Step D. MS (LCMS) m/z 425.2 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 0.89-1.00 (m, 3 H) 1.57-1.76 (m, 5 H) 2.29-2.45 (m, 1H) 2.55-2.69 (m, 3 H) 3.09 (s, 3 H) 3.86-4.04 (m, 1 H) 4.17-4.34 (m, 1H) 6.63 (d, J=7.02 Hz, 1 H) 7.31 (d, J=8.00 Hz, 2 H) 7.44-7.55 (m, 2 H)7.85 (d, J=5.85 Hz, 1 H).

Example 12(2R)-4-{5-Fluoro-2-oxo-4-[4-(pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-{5-Fluoro-2-oxo-4-[4-(pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

1,4-Dioxane was added to 1-bromo-4-(pentafluoro-6λ-sulfanyl)benzene (500mg, 1.77 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (628 mg, 2.47mmol), potassium acetate (347 mg, 3.53 mmol) and Pd(dppf)Cl₂ (130 mg,0.177 mmol). The mixture was heated to 80° C. and stirred at thistemperature for 3 h.(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (456 mg, 0.883 mmol) and aq Na₂CO₃ (2.0 N, 1.77 mL, 3.53 mmol) wereadded and the reaction was stirred at 80° C. overnight. The mixture wasdiluted with EtOAc and washed with brine. The organics were dried(MgSO₄), filtered, and concentrated. The crude residue was purified viaflash chromatography using a 40 g silica column and an eluent of EtOAcin n-heptane (0-100%) to afford the title compound (205 mg, 39.2%). MS(LCMS) m/z 591.4 (M−1).

Step B)(2R)-4-{5-Fluoro-2-oxo-4-[4-(pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Aqueous HCl (1.0 M) was added to a solution of(2R)-4-{5-fluoro-2-oxo-4-[4-(pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(81 mg, 0.14 mmol) and the reaction was stirred at rt overnight. Thereaction was concentrated in vacuo to afford the title compound as asolid (70 mg, 100%). MS (LCMS) m/z 509.1 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.58 (s, 3 H) 2.06-2.26 (m, 1 H) 3.11 (s, 3 H) 3.70-3.89(m, 1 H) 3.97-4.14 (m, 1 H) 6.64 (d, J=7.41 Hz, 1 H) 7.81 (d, 2 H) 8.04(d, J=8.78 Hz, 2 H) 8.11 (d, J=6.44 Hz, 1 H).

Example 13(2R)-4-[5-Fluoro-4-(3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (510 mg, 55%) was obtained as a gum from(3-methylphenyl)boronic acid (384 mg, 2.82 mmol) using a procedureanalogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 479.4 (M−1).

Step B)(2R)-4-[5-Fluoro-4-(3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (255 mg, 61%) was obtained as a solid from(2R)-4-[5-fluoro-4-(3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(510 mg, 1.06 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 9, Step D. MS (LCMS) m/z 397.1 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.70 (s, 3 H) 2.28-2.44 (m, 4 H) 2.62 (dd, J=10.44,5.37 Hz, 1 H) 3.09 (s, 3 H) 3.96 (ddd, J=12.98, 10.63, 5.46 Hz, 1 H)4.19-4.35 (m, 1 H) 6.64 (d, J=7.22 Hz, 1 H) 7.27-7.45 (m, 4 H) 7.88 (d,J=5.85 Hz, 1 H).

Example 14(2R)-4-[5-Fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (360 mg, 38%) was obtained as a gum from(4-fluoro-3-methylphenyl)boronic acid (434 mg, 2.82 mmol) using aprocedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 1, Step B. MS (LCMS) m/z 497.0 (M−1).

Step B)(2R)-4-[5-Fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-1-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (271 mg, 91%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(360 mg, 0.722 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 9, Step D. MS (LCMS) m/z 415.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.13 (ddd, J=13.12, 11.17, 4.98 Hz, 1 H) 2.26 (s, 3H) 2.40-2.45 (m, 1 H) 3.08 (s, 3 H) 3.75 (td, J=11.85, 5.17 Hz, 1 H)4.02 (td, J=11.85, 4.98 Hz, 1 H) 6.49 (d, J=7.61 Hz, 1 H) 7.20-7.28 (m,1 H) 7.38-7.45 (m, 1 H) 7.50 (d, J=7.41 Hz, 1 H) 8.01 (d, J=6.63 Hz, 1H).

Example 155-Fluoro-1-[(3R)-3-(hydroxyamino)-3-(methylsulfonyl)butyl]-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one

Step A) 3-(4-Bromophenoxy)oxetane

4-Bromophenol (2.5 g, 14.5 mmol) and K₂CO₃ (5.45 g, 39.4 mmol) wereadded to a solution of oxetan-3-yl 4-methylbenzenesulfonate (3.00 g,13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to100° C. and stirred at this temperature for 24 h. The reaction wasdiluted with EtOAc and washed with water. The organic layer was dried(MgSO₄), filtered and concentrated to afford the title compound. MS(GCMS) m/z 228. This material was used in subsequent steps withoutfurther purification.

Step B)4,4,5,5-Tetramethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborolane

The title compound (3.11 g, 86%) was obtained from3-(4-bromophenoxy)oxetane (3.00 g, 13.1 mmol) using a procedureanalogous to that described for2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole,Example 1, Step A. MS (GCMS) m/z 276. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.31 (s, 12 H) 4.70-4.79 (m, 2 H) 4.91-5.00 (m, 2 H) 5.18-5.27 (m, 1H) 6.67 (d, J=8.78 Hz, 2 H) 7.73 (d, J=8.78 Hz, 2 H).

Step C)5-Fluoro-1-{(3R)-3-(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one

1,4-Dioxane (20 mL) and water (5 mL) were added to a flask containing(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3 (287 mg, 0.56 mmol),4,4,5,5-tetramethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborolane(301 mg, 1.09 mmol), Pd(PPh₃)₄ (65 mg, 0.06 mmol), and potassiumcarbonate (230 mg, 1.67 mmol), which was previously flushed with N₂. Themixture was heated to 80° C. and stirred at that temperature overnight.The reaction was concentrated and purified via flash chromatographyusing two 12 g silica gel columns. The first column was eluted withmethanol in dichloromethane (0-20%). The second column was eluted withEtOAc in n-heptane (0-100%) followed by methanol in dichloromethane(0-20%) to afford the title compound as a solid (164 mg, 54%). MS (LCMS)m/z 537.4 (M−1).

Step D)5-Fluoro-1-[(3R)-3-(hydroxyamino)-3-(methylsulfonyl)butyl]-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one

Trifluoroacetic acid (1 mL) was added to a solution of5-fluoro-1-{(3R)-3-(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one(164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir atrt overnight and then concentrated under vacuum. The residue wasre-dissolved in dichloromethane and n-heptane and concentrated again toafford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1(M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.69 (s, 3 H) 2.35 (ddd,J=13.66, 10.63, 5.17 Hz, 1 H) 2.53-2.67 (m, 1 H) 3.09 (s, 3 H) 3.91(ddd, J=12.98, 10.63, 5.27 Hz, 1 H) 4.16-4.30 (m, 1 H) 4.69 (dd, J=7.51,4.78 Hz, 2 H) 5.02 (t, J=6.73 Hz, 2 H) 5.33 (t, J=5.46 Hz, 1 H) 6.58 (d,J=7.42 Hz, 1 H) 6.85-6.91 (m, 2 H) 7.55 (dd, J=8.68, 1.85 Hz, 2 H) 7.80(d, J=6.24 Hz, 1 H).

Example 16(2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

To a 3 L flask with mechanical stirring was added ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2 (100 g, 225 mmol), (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146mmol) and Pd(dppf)₂Cl₂ (4.93 g, 6.74 mmol). The flask was purged withN₂, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K₃PO₄ (225mL, 674 mmol) were added. The reaction mixture was heated to 75° C. andstirred at this temperature for 30 min. Additional(4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) was added andthe reaction was allowed to heat for 1.5 h. The mixture was allowed tocool to rt and the aqueous layer was separated. The organic layer waspassed through a celite pad and placed back in the reaction vessel.Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and themixture was heated to 50° C. and stirred at this temperature for 1 h.The mixture was allowed to cool and the aqueous layer separated. Celitewas added to the aqueous layer and the mixture was filtered through aplug of celite. The filtrate was placed in a flask with overhead stirrerand carefully acidified with 4 M aq HCl and heated to 50° C. withstirring until a precipitate formed. The solid was collected viafiltration and dried under vacuum to afford the title compound as a tansolid (68.7 g, 74%). MS (LCMS) m/z 420.6 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.54 (s, 3 H) 2.18 (ddd, J=13.17, 10.24, 5.07 Hz, 1 H)2.41-2.45 (m, 1 H) 3.10-3.19 (s, 3 H) 3.87-4.08 (m, 2 H) 6.47 (d, J=7.02Hz, 1 H) 7.42 (dd, J=8.39, 1.95 Hz, 1 H) 7.48-7.56 (m, 1 H) 7.60 (dd,J=9.95, 1.95 Hz, 1 H) 8.06 (d, J=6.05 Hz, 1 H).

Step B)(2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N-Methylmorpholine (54 mL, 491 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (43.1 g, 245 mmol) were added to asolution of(2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (68.7 g, 164 mmol) in 2-methyltetrahydrofuran (1 L) and thereaction was stirred at rt for 2 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (28.8 g, 245 mmol) was addedand the reaction was allowed to stir at rt for 1 h. The mixture wasfiltered and the filtrate was concentrated. The crude residue waspurified via column chromatography using silica gel and eluting with 40%EtOAc in n-heptane (4 L) and EtOAc (6 L). The desired fractions werecombined and concentrated to afford the title compound as a white gummysolid. (74.82 g, 88%). MS (LCMS) m/z 517.9 (M−1).

Step C)(2R)-4-[4-(4-Chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Water (312 mL) and 1 N aq HCl (23.9 mL, 23.9 mmol) were added to asolution of(2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(74.7 g, 144.1 mmol) in ethanol (126 mL). The reaction was heated to 70°C. and stirred at this temperature overnight. The reaction was allowedto cool and the solid was collected via filtration and washed with wateruntil the filtrate had a pH of −5. The solid was dried under vacuum toafford the title compound as a white solid (46.48 g, 74%). MS (LCMS) m/z435.6 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3 H) 2.09-2.21 (m,1 H) 2.44 (d, J=5.27 Hz, 1 H) 3.10 (s, 3 H) 3.77 (td, J=11.90, 5.07 Hz,1 H) 4.04 (td, J=11.95, 4.98 Hz, 1 H) 6.51 (d, J=7.02 Hz, 1 H) 7.44 (dd,J=8.29, 2.05 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.62 (dd, J=9.95, 1.95 Hz, 1 H)8.04 (d, J=5.85 Hz, 1 H) 9.22 (s, 1 H) 11.05 (s, 1 H).

Example 17(2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (5.90 g, 7.22 mmol) was added to a mixture ofethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2 (29.63 g, 66.55 mmol), (2-fluoro-3-methoxyphenyl)boronic acid (18.50g, 108.9 mmol) and potassium phosphate tribasic (54.5 g, 205 mmol) in2-methyltetrahydrofuran (450 mL) and deionized water (225 mL). Themixture was heated to 60° C. and stirred at this temperature overnight.The reaction was allowed to cool to rt. The aqueous layer was separatedfrom the organics and the organics were washed with water (200 mL) andbrine (200 mL), dried (MgSO₄), and filtered. Darco® G-60-100 mesh,powder was added to the filtrate and was stirred for 1 h. Solids wereremoved via filtration over celite and the filtered pad was washed withEtOAc (−300 mL). The combined filtrates were concentrated to afford ared oil (30.62 g). The oil was dissolved in 2-methyltetrahydrofuran (450mL) and deionized water (225 mL). Potassium hydroxide (26.1 g, 465 mmol)was added to the mixture and the reaction was heated to 50° C. andstirred at this temperature overnight. The reaction was allowed to coolto rt. The aqueous layer was separated and washed with diethyl ether(2×200 mL). The aqueous layer was slowly acidified while stirring usingconcentrated HCl to a pH of 1 and the suspension was stirred for 1 h.The suspension was filtered and the solids were washed with water (3×100mL) and hexanes (3×300 mL). The solids were dried in vacuo to afford thetitle compound as a tan solid (26.49 g, 94.54%). MS (LCMS) m/z 416.0(M+1). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.57 (s, 3 H) 2.14-2.28 (m, 0 H)2.42-2.54 (m, 1 H) 3.18 (s, 3 H) 3.88 (s, 3 H) 3.90-4.09 (m, 2 H) 6.44(d, J=7.03 Hz, 1 H) 6.92-7.04 (m, 1 H) 7.20-7.36 (m, 2 H) 8.06 (d,J=5.95 Hz, 1 H) 13.90 (br. s., 1 H).

Step B)(2R)-4-[5-Fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N-Methylmorpholine (11 mL, 96.2 mmol) was added to a solution of CDMT(13.5 g, 116 mmol) and(2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (26.49 g, 63.77 mmol) in 2-methyltetrahydrofuran (640 mL) and thereaction was stirred for 2 h. THP-hydroxylamine (13.5 g, 116 mmol) wasadded to the reaction and the reaction was stirred overnight at rt. Thereaction was quenched with saturated aqueous sodium bicarbonate (500mL). The organic layer was separated and washed with water (300 mL) andbrine (300 mL), then dried (MgSO₄), and filtered. Darco G-60, -100 mesh,powder was added to the filtrate and the suspension was stirred for 1 h.The charcoal was removed via filtration through a celite pad and thefilter pad was washed with EtOAc (1 L). The filtrate was concentrated toafford the title compound as a yellowish-white solid (30.49, 92.93%). MS(LCMS) m/z 513.9 (M−1).

Step C)(2R)-4-[5-Fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Pyridinium p-toluenesulfonate (190 mg, 0.76 mmol) was added to asolution of(2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(777 mg, 1.51 mmol) in ethanol (15 mL). The reaction was heated to 50°C. and stirred at this temperature overnight. Additional pyridiniump-toluenesulfonate (118 mg, 0.47 mmol) was added to the solution and thereaction was heated at 60° C. for 3 h. The reaction was allowed to coolto rt and the precipitate was collected via filtration. The solid waswashed with ethanol (15 mL) and hexanes (15 mL) and dried in vacuo toafford the title compound as a white solid (413 mg, 63.5%). MS (LCMS)m/z 431.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (s, 1 H) 2.08-2.25(m, 0 H) 2.41-2.56 (m, 1 H) 3.02-3.19 (m, 3 H) 3.71-3.85 (m, 1 H) 3.88(s, 3 H) 3.98-4.13 (m, 1 H) 6.47 (d, J=7.02 Hz, 1 H) 6.93-7.08 (m, 1 H)7.19-7.36 (m, 2 H) 8.04 (d, J=5.66 Hz, 1 H) 9.24 (d, J=1.56 Hz, 1 H)11.07 (d, J=1.56 Hz, 1 H).

Example 18(2R)-4-[5-Fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) Ethyl 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate

Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to asolution of ethyl 4-hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol)and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL) and thereaction was stirred at rt for 16 h. The reaction was quenched withsaturated aq NaHCO₃. The layers were separated and the organic layer waswashed with water. The organic layer was dried (Na₂SO₄), filtered, andconcentrated. Purification via flash chromatography on a 200 g silicacolumn using an eluent of EtOAc in hexanes (5-10%) afforded the titlecompound as a clear oil (11.1 g, 85%).

Step B) [cis-4-(Tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol and(+/−)-[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol

Sodium borohydride (3.69 g, 97.5 mmol) was added to a solution of ethyl4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate (2.50 g, 9.75mmol) in ethanol (100 mL) at 0° C. The reaction was allowed to warm tort as the ice bath expired. After 2 days the reaction was cooled to 0°C. and quenched by the addition of 1 N aq HCl until the effervescenceceased, pH 5-6. The reaction was concentrated and the resulting residuewas partitioned between EtOAc and water. The layers were separated, andthe aqueous layer was extracted with EtOAc. The organic layers werecombined, dried (MgSO₄), filtered, and concentrated. Purification on asilica gel 100 g column and an eluent of EtOAc in hexanes (10-40%)afforded the two sets of enantiomers as clear oils.

(+/−)-[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (387 mg,18%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.65 (m, 12 H) 1.64-1.76(m, 1 H) 1.76-1.94 (m, 3 H) 3.33-3.64 (m, 3 H) 3.80-4.01 (m, 2 H)4.59-4.75 (m, 1 H).

(+/−)-[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (824,39.4%) ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86-1.11 (m, 2 H) 1.16-1.31(m, 1 H) 1.31-1.64 (m, 7 H) 1.64-1.77 (m, 1 H) 1.78-1.93 (m, 3 H)1.99-2.14 (m, 2 H) 3.35-3.67 (m, 4 H) 3.80-4.04 (m, 1 H) 4.63-4.79 (m, 1H).

Step C)2-[(trans-4-{[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran

Diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) was added to a solutionof [trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (2.05 g,9.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.3g, 10.7 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and triethylamine(1.5 mL, 10.5 mmol) in THF (150 mL) at 0° C. The reaction was allowed towarm to rt and stirred overnight. Water (200 mL) was added and thereaction was extracted with EtOAc (600 mL). The organics were washedwith 1 M aq NaOH (4×100 mL), brine, then dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude residue was purified viaflash chromatography using an eluent of 20% EtOAc in hexanes to affordthe title compound as a white solid (1.9 g, 48%). MS (APCI) m/z 417.3(M+1).

Step D) Ethyl(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate

Pd(dppf)Cl₂ (350 mg, 0.431 mmol) was added to a solution of ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(1.6 g, 3.6 mmol),2-[(trans-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran(1.9 g, 4.49 mmol), and potassium phosphate tribasic (2.9 g, 10.8 mmol)in 2-methyl tetrahydrofuran/water (5:1, 240 mL). The reaction mixturewas heated to 80° C. and stirred at this temperature for 16 h. Thereaction was allowed to cool to rt, and water (50 mL) was added. Themixture was extracted with EtOAc (3×150 mL). The combined organic phaseswere dried (Na₂SO₄), filtered, and concentrated under reduced pressureto afford the title compound as a light tan solid (1.4 g, 64%). MS(LCMS) m/z 608.2 (M+1).

Step E)(2R)-4-[5-Fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

Aqueous lithium hydroxide (2.0 M, 5.8 mL, 2.3 mmol) was added to asolution of ethyl(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate(1.4 g, 2.3 mmol) in ethanol (40 mL). The reaction was heated to 50° C.for 3 h. The reaction was allowed to cool to ambient temperature andthen acidified to a pH of ˜3 with 1.0 N aq. HCl. The mixture wasextracted with EtOAc (3×150 mL). The combined organic phases were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordthe title compound as a white solid (1.28 g, 98%). MS (LCMS) m/z 580.3(M+1).

Step F)(2R)-4-[5-Fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N-Methyl morpholine (340 uL, 3.09 mmol) was added to a suspension of(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (1.28 g, 2.21 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (510 mg,2.87 mmol) in 2-methyltetrahydrofuran (30 mL) and the reaction wasstirred for 1 h at rt. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (61 mg,0.52 mmol) was added, and the reaction was stirred overnight at rt.Water (50 mL) was added, and the mixture was extracted with EtOAc (3×150mL). The combined organic phases were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The crude material was purified viaflash chromatography using an eluent of EtOAc in n-heptane (75-100%) toafford the title compound as a light brown residue (700 mg, 46%). MS(LCMS) m/z 677.4 (M+1).

Step G)(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Hydrochloric acid (4.0 M in 1, 4-dioxane, 1.7 mL, 6.63 mmol) was addedto a solution of(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)-pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(450 mg, 0.66 mmol) in 1,4-dioxane:DCM:water (2:2:1, 5 mL) at roomtemperature. After 1 h, the reaction was concentrated under reducedpressure. The crude residue was triturated in ethanol (10 mL) overnight.The solid was collected via filtration, washed with ethanol (5 mL), anddried under reduced pressure to afford the title compound as a whitesolid (110 mg, 33%). MS (LCMS) m/z 511.1 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.97-1.19 (m, 4 H) 1.54 (s, 3 H) 1.58-1.72 (m, 1 H)1.72-1.89 (m, 4 H) 2.04-2.23 (m, 1 H) 2.41 (m, 1 H) 3.08 (s, 3 H)3.18-3.40 (m, 1 H) 3.65-3.84 (m, 3 H) 4.01 (td, J=11.61, 4.88 Hz, 1 H)4.49 (br. s., 1 H) 6.45 (d, J=7.81 Hz, 1 H) 6.94-7.06 (m, 2 H) 7.36-7.54(m, 2 H) 7.96 (d, J=6.83 Hz, 1 H) 9.21 (s, 1 H) 11.07 (s, 1 H) 11.12 (s,1 H).

Example 19(2R)-4-[5-Fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Pd Encat™ (580 mg, 0.17 mmol) was added to a mixture of potassiumcarbonate (723 mg, 5.2 mmol), (3-fluoro-4-methoxyphenyl)boronic acid(318 mg, 2.1 mmol), and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (900 mg, 1.7 mmol) in 1,4-dioxane:water (5:1, 24 mL). The reactionwas heated to 80° C. and allowed to stir at this temperature overnight.The reaction was filtered through a pad of celite, which was washed withmethanol (250 mL). The filtrate was concentrated under reduced pressure,and the resulting crude material was purified via flash chromatographyusing an eluent of EtOAc in heptanes (20-100%), then 10% methanol inEtOAc to provide the title compound as a light tan residue (800 mg,99%). MS (LCMS) m/z 495.1 (M−1).

Step B)(2R)-4-[5-Fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (400 mg, 58%) was obtained as a solid from(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(800 mg, 1.65 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 413.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.06-2.18 (m, 1 H) 2.38-2.47 (m, 1 H) 3.08 (s, 3 H)3.74 (td, J=12.00, 4.88 Hz, 1 H) 3.87 (s, 3 H) 4.02 (td, J=11.85, 4.98Hz, 1 H) 6.52 (d, J=7.81 Hz, 1 H) 7.21-7.31 (m, 1 H) 7.34-7.51 (m, 2 H)7.99 (d, J=6.83 Hz, 1 H) 9.20 (s, 1 H) 11.06 (br. s, 1 H).

Example 20(2R)-4-[5-Fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine

A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol),2,2′-(1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (5.1 g,16.0 mmol), 1.0 M aq K₃PO₄ (28.3 mL, 28.3 mmol), and Pd(PPh₃)₄ (330 mg,0.31 mmol) in DMF (140 mL) was heated to 80° C. and stirred at thistemperature for 16 h. Water (100 mL) was added to the reaction mixtureand was extracted with EtOAc (3×200 mL). The combined organic phaseswere dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The crude material was purified via flash chromatography using an eluentof 17% EtOAc in n-heptane to afford the title compound as a white solid(0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.36 (s, 12 H) 7.19 (t, J=4.68 Hz, 1 H) 7.93 (d, J=8.00 Hz, 2 H)8.43 (d, J=7.81 Hz, 2 H) 8.81 (d, J=4.68 Hz, 2 H).

Step B) Ethyl(2R)-4-[5-Fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate

The title compound (278 mg, 87%) was obtained as a light tan solid from2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine (270mg, 0.94 mmol) and ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2, (300 mg, 0.67 mmol) using a procedure analogous to that describedfor the preparation of ethyl(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate,Example 18, Step D. MS (LCMS) m/z 474.2 (M+1).

Step C)(2R)-4-[5-Fluoro-2-oxo-4-(4-pyridin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

The title compound (250 mg, 98%) was obtained as a light brown gum fromethyl(2R)-4-[5-fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate(270 mg, 0.57 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid, Example 18, Step E. MS (LCMS) m/z 446.1 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.73 (s, 3 H) 2.39-2.51 (m, 1 H) 2.62-2.75 (m, 1 H)3.17 (s, 3 H) 4.20-4.46 (m, 2 H) 6.86 (d, J=7.02 Hz, 1 H) 7.65 (t,J=5.07 Hz, 1 H) 7.83 (d, J=7.02 Hz, 2 H) 8.09 (d, J=5.85 Hz, 1 H) 8.53(d, J=8.39 Hz, 2 H) 9.06 (d, J=4.88 Hz, 2 H).

Step D)(2R)-4-[5-Fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (290 mg, 94%) was obtained as a light brown gum from(2R)-4-[5-fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (250 mg, 0.56 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(87 mg, 0.74 mmol) using a procedure analogous to that described for thepreparation of(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 18, Step F. MS (LCMS) m/z 543.0 (M+1).

Step E)(2R)-4-[5-Fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (80 mg, 30%) was obtained as a tan solid from(2R)-4-[5-fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(312 mg, 0.57 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 461.1 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.70 (s, 3 H) 2.31-2.45 (m, 1 H) 2.56-2.71 (m, 1 H)3.10 (s, 3 H) 3.87-4.01 (m, 1 H) 4.19-4.33 (m, 1 H) 6.70 (d, J=7.42 Hz,1 H) 7.38 (t, J=4.88 Hz, 1 H) 7.73 (dd, J=8.59, 1.76 Hz, 2 H) 7.87 (d,J=6.05 Hz, 1 H) 8.53 (d, J=8.59 Hz, 2 H) 8.87 (d, J=4.88 Hz, 2 H).

Example 21(2R)-4-{5-Fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)5-Methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine

The title compound (700 mg, 17%) was obtained as a white solid from2-chloro-5-methoxypyrimidine (1.85 g, 12.8 mmol) and2,2′-(1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (6.9 g,21.0 mmol) using a procedure analogous to that described for thepreparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine,Example 20, Step A. MS (LCMS) m/z 313.1 (M+1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.33 (s, 12 H) 3.93 (s, 3 H) 7.83-7.90 (m, 2 H)8.28-8.34 (m, 2 H) 8.45 (s, 2 H).

Step B)(2R)-4-{5-Fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (900 mg, 95%) was obtained as a tan solid from5-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine(719 mg, 2.3 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (850 mg, 1.65 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19 Step A. MS (LCMS) m/z 573.2 (M+1).

Step C)(2R)-4-{5-Fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (50 mg, 6%) was obtained as a light brown solid from(2R)-4-{5-fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(900 mg, 1.57 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 491.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.53 (s, 3 H) 2.08-2.19 (m, 1 H) 2.39-2.48 (m, 1 H) 3.07 (s, 3 H)3.69-3.78 (m, 1 H) 3.92 (s, 3 H) 3.96-4.08 (m, 1 H) 6.56 (d, J=7.71 Hz,1 H) 7.67 (m, J=8.70, 2.00 Hz, 2 H) 8.01 (d, J=6.54 Hz, 1 H) 8.34-8.38(m, 2 H) 8.64 (s, 2 H) 9.19 (br. d, J=1.80 Hz, 1 H) 11.04 (br. d, J=1.90Hz, 1 H).

Example 22(2R)-4-{5-Fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) 2-(4-Bromophenyl)-4-methoxy-2H-1,2,3-triazole

Cesium carbonate (4.5 g, 13.7 mmol) was added to a solution of2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (1.1 g, 4.6 mmol) and methyliodide (0.36 mL, 5.7 mmol) in THF (50 mL). The reaction was heated to60° C. and stirred at this temperature for 16 h. Water (20 mL) was addedto the reaction, and the resulting mixture was extracted with EtOAc(2×150 mL). The combined organic phases were dried over potassiumcarbonate, filtered, and concentrated under reduced pressure to affordthe title compound as a tan solid (1.1 g, 95%). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 3.98 (s, 3 H) 7.39 (s, 1 H) 7.55-7.62 (m, 2 H)7.79-7.86 (m, 2 H).

Step B)4-Methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole

Pd(dppf)Cl₂ (0.71 g, 0.87 mmol) was added to a mixture of2-(4-bromophenyl)-4-methoxy-2H-1,2,3-triazole (1.1 g, 2.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.3 g, 5.2mmol), potassium acetate (1.3 g, 13.0 mmol), in 2-methyltetrahydrofuran:water (5:1, 60 mL). The reaction was heated to 80° C.and stirred at this temperature for 16 h. The reaction was allowed tocool to rt, and water (50 mL) was added. The reaction was filteredthrough celite, which was washed with EtOAc (150 mL). The filtrate wasconcentrated under reduced pressure, and the resulting crude materialwas purified by flash chromatography using an eluent of EtOAc inn-heptane (10-60%) to afford the title compound as a light tan solid(1.2 g, 92%). MS (LCMS) m/z 302.3 (M+1). ¹H NMR (400 MHz, METHANOL-d₄)ppm 1.33 (s, 12 H) 4.01 (s, 3 H) 7.40 (s, 1 H) 7.78-7.84 (m, 2 H)7.88-7.95 (m, 2 H).

Step C)(2R)-4-{5-Fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (1.15 mg, 88%) was obtained as tan solid from4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole(0.98 g, 1.4 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (1.2 g, 2.3 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19 Step A. MS (LCMS) m/z 562.0 (M+1).

Step D)(2R)-4-{5-Fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (700 mg, 70%) was obtained as a light tan solid from(2R)-4-{5-fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(1.15 g, 2.04 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 480.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆)ppm 1.53 (s, 3 H) 2.07-2.18 (m, 1 H) 2.39-2.48 (m, 1 H) 3.06 (s, 3 H)3.69-3.77 (m, 1 H) 3.95 (s, 3 H) 3.97-4.08 (m, 1 H) 6.54 (d, J=7.62 Hz,1 H) 7.65-7.73 (m, 2 H) 7.75 (s, 1 H) 7.90-7.98 (m, 2 H) 8.03 (d, J=6.64Hz, 1 H) 11.06 (br. s., 1 H).

Example 23(2R)-4-{5-Fluoro-4-[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)4-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole

Pd(dppf)Cl₂ (592 mg, 0.718 mmol) was added to a solution of potassiumacetate (705 mg, 7.18 mmol),2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole (600 mg, 2.52 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (729 mg, 2.87mmol) in 1,4-dioxane (20 mL). The reaction was heated to 80° C. andstirred at this temperature for 16 h. The reaction was filtered throughcelite, and the filter pad was washed with EtOAc (150 mL). The combinedfiltrates were concentrated under reduced pressure, and the crudematerial was purified via flash chromatography using EtOAc in n-heptane(10-60%) to afford the title compound as a light tan solid (720 mg,98%). MS (LCMS) m/z 286.2 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.32 (s, 12 H) 2.36 (s, 3 H) 7.66 (s, 1 H) 7.77-7.84 (m, 2 H) 7.92-8.00(m, 2 H).

Step B)(2R)-4-{5-Fluoro-4-[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (0.99 g, 98%) was obtained as a tan gum from4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole(0.70 g, 2.4 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (0.90 g, 2.0 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 546.5 (M+1).

Step C)(2R)-4-{5-Fluoro-4-[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (450 mg, 53%) was obtained as a tan solid from(2R)-4-{5-fluoro-4-[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(0.99 g, 1.81 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 464.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.53 (s, 3 H) 2.06-2.20 (m, 1 H) 2.33 (br. s, 3 H) 2.38-2.49 (m, 1H) 3.06 (s, 3 H) 3.68-3.80 (m, 1 H) 3.90-4.11 (m, 1 H) 6.55 (d, J=7.61Hz, 1 H) 7.65-7.76 (m, 2 H) 7.90 (br. s, 1 H) 7.96-8.10 (m, 2 H) 11.05(br. s., 1 H).

Example 24(2R)-4-(5-Fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-(5-Fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (480 mg, 95%) was obtained as a light brown gum from6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (347 mg, 1.36mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (500 mg, 0.97 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19 Step A. MS (LCMS) m/z 517.1 (M+1).

Step B)(2R)-4-(5-Fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (110 mg, 28%) was obtained as a light tan solid from(2R)-4-(5-fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(0.48 g, 0.93 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 433.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.09-2.19 (m, 1 H) 2.44-2.52 (m, 1 H) 3.07 (s, 3 H)3.73-3.84 (m, 1 H) 4.04 (m, 1 H) 6.71 (d, J=7.61 Hz, 1 H) 7.99 (dt,J=8.76, 1.96 Hz, 1 H) 8.06-8.10 (m, 1 H) 8.17 (d, J=8.78 Hz, 1 H) 8.26(t, J=1.71 Hz, 1 H) 8.89-9.05 (m, 2 H) 9.20 (br. s., 1 H) 11.03 (br. s.,1 H).

Example 25(2R)-4-[5-Fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (800 mg, 99%) was obtained as a light tan gum from(3-methoxyphenyl)boronic acid (318 mg, 2.09 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (900 mg, 1.74 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 495.1 (M+1).

Step B)(2R)-4-[5-Fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (400 mg, 58%) was obtained as a tan solid from(2R)-4-[5-fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(0.82 g, 1.65 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 18, Step G. MS (LCMS) m/z 413.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.52 (s, 3 H) 2.05-2.18 (m, 1 H) 2.36-2.50 (m, 1 H) 3.06 (s, 3 H)3.66-3.78 (m, 4 H) 3.95-4.08 (m, 1 H) 6.50 (d, J=7.61 Hz, 1 H) 6.98-7.11(m, 3 H) 7.32-7.40 (m, 1 H) 7.98 (d, J=6.54 Hz, 1 H) 9.18 (br. s., 1 H)11.04 (s, 1 H).

Example 26(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole

Pd(dppf)Cl₂ (280 mg, 0.343 mmol) was added to a mixture of2-(4-bromophenyl)-2H-1,2,3-triazole (255 mg, 1.14 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (350 mg, 1.38mmol), and potassium acetate (340 mg, 3.46 mmol) in 1,4-dioxane (10 mL).The reaction was heated to 80° C. and stirred at this temperatureovernight. The reaction was allowed to cool to rt and was diluted withEtOAc (30 mL) and brine (30 mL). The mixture was filtered throughcelite, and the organic layer was separated from the filtrate. Theaqueous layer was extracted with EtOAc (2×30 mL) and the organics werecombined, dried (MgSO₄), filtered and concentrated. The crude materialwas purified via flash chromatography using an Analogix SF15-12 g columnand an eluent of EtOAc in n-heptane (0-10%) to afford the title compoundas an orange solid (240.6 mg, 78.0%). MS (LCMS) m/z 272.4 (M+1). ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 12 H) 7.83 (s, 2 H) 7.94 (d, 2 H)8.10 (d, J=8.59 Hz, 2 H).

Step B) Ethyl(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate

Pd(dppf)Cl₂ (484 mg, 0.59 mmol) was added to a mixture of ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2, (2.20 g, 4.94 mmol),2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole(2.01 g, 7.41 mmol), and potassium phosphate (3.95 g, 14.8 mmol) in2-methyltetrahydrofuran (200 mL) and deionized water (40 mL). Thereaction was heated to 60° C. and was vigorously stirred at thistemperature overnight. The reaction was diluted with EtOAc (100 mL) andwater (100 mL) and was filtered through a celite pad (˜1 inch). Thefilter pad was washed with EtOAc (100 mL) and the filtrates werecombined. The aqueous layer was separated and was extracted with EtOAc(2×100 mL). The combined organics were washed with brine (100 mL), dried(MgSO₄), filtered and concentrated. The crude material was purified viaflash chromatography using a Varian SF25-40 g column and an eluent ofEtOAc in hexanes (30-100%) to afford the title compound as a yellowsolid (1.54 g, 67.4%). MS (LCMS) m/z 463.0 (M+1). ¹H NMR (400 MHz,DMSO-d₆) ppm 1.23 (t, 3 H) 1.62 (s, 3 H) 2.18-2.32 (m, 1 H) 2.52-2.66(m, 1 H) 3.16 (s, 3 H) 3.92-4.07 (m, 2 H) 4.08-4.24 (m, 2 H) 6.59 (d,J=7.81 Hz, 1 H) 7.72-7.84 (m, 2 H) 8.10 (d, J=6.63 Hz, 1 H) 8.12-8.17(m, 2 H) 8.18 (s, 2 H).

Step C)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid

Potassium hydroxide (1.30 g, 23.2 mmol) was added to a solution of ethyl(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate(1.54 g, 3.33 mmol) in 2-methyltetrahydrofuran:water (2::1 42.5 mL) andthe solution was stirred at rt overnight. Methanol (5 mL) was added andthe reaction was heated to 60° C. The reaction mixture was stirred atthis temperature for 2 h. The reaction was concentrated and trituratedin 3 M aq HCl. The solid was collected via filtration and washed withwater (20 mL) and hexanes (20 mL). The solid was dried under vacuum toafford the title compound as a white solid (1.39 g, 96.1%). MS (LCMS)m/z 435.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 3 H) 2.13-2.30(m, 0 H) 2.41-2.61 (m, 1 H) 3.17 (s, 3 H) 3.89-4.13 (m, 2 H) 6.59 (d,J=7.81 Hz, 1 H) 6.56-6.63 (m, 1 H) 7.79 (dd, J=8.78, 1.76 Hz, 3 H) 8.09(d, J=6.83 Hz, 1 H) 8.12-8.17 (m, 2 H) 8.19 (s, 2 H).

Step D)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

N-Methylmorpholine (540 μL, 4.9 mmol) was added to a solution of CDMT(750 mg, 4.27 mmol) and(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanoicacid (1.39 g, 3.20 mmol) in 2-methyltetrahydrofuran (30 mL) and thereaction was stirred for 1 h at rt.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (670 mg, 5.72 mmol) was addedto the reaction and the reaction was stirred overnight at rt. Thereaction was quenched with saturated aq NaHCO₃ (100 mL) and the aqueouslayer was extracted with EtOAc (3×100 mL). The combined organics werewashed with brine (100 mL), dried (MgSO₄), filtered and concentrated.The crude product was purified via flash chromatography using a VarianSF25-40 g column and eluent of EtOAc in hexanes (30-100%) to afford thetitle compound as a white solid (1.53 g, 89.6%). MS (LCMS) m/z 532.2(M−1).

Step E)(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Pyridinium p-toluenesulfonate (360 mg, 0.50 mmol) was added to asolution of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(1.53 g, 2.87 mmol) in ethanol (60 mL). The solution was heated to 70°C. and was stirred at this temperature for 3 h. The reaction was allowedto cool and was stirred at rt for three days. The solid was collectedvia filtration, washed with ethanol (20 mL) and hexanes (20 mL). Thesolid was dried under vacuum to afford the title compound as a whitesolid (1.05 g, 81.5%). MS (LCMS) m/z 450.0 (M+1), ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.58 (s, 3 H) 2.08-2.27 (m, 0 H) 2.38-2.59 (m, 1 H) 3.12(s, 3 H) 3.72-3.90 (m, 1 H) 4.00-4.17 (m, 1 H) 6.62 (d, J=7.61 Hz, 1 H)7.70-7.88 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.12-8.18 (m, 2 H) 8.19 (s,2 H) 9.25 (d, J=1.95 Hz, 1 H) 11.09 (d, J=1.76 Hz, 1 H).

Example 27(2R)-4-[5-Fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (1.5 g, 94%) was obtained from(2-fluoro-4-methoxyphenyl)boronic acid (737 mg, 4.34 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (1.6 g, 3.1 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 513.3 (M+1).

Step B)(2R)-4-[5-Fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

A solution of HCl (4 M in 1,4-dioxane, 4.4 mL, 17.5 mmol) was added to asolution of(2R)-4-[5-fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(1.5 g, 2.9 mmol) in 1,4-dioxane (20 mL), DCM (20 mL), and water (5 mL)and the reaction was stirred for 20 min at rt. The reaction wasconcentrated under reduced pressure, isopropyl alcohol (10 mL) was addedto the residue and the mixture was concentrated. Isopropyl alcohol (30mL) was added to the residue and the solution was stirred overnight atrt to afford a precipitate. The precipitate was collected viafiltration, washed with isopropyl alcohol, and dried under vacuum toafford the title compound as a light brown solid (725 mg, 58%) MS (LCMS)m/z 431.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.07-2.25(m, 1 H) 2.42-2.48 (m, 1 H) 3.11 (s, 3 H) 3.71-3.81 (m, 1 H) 3.83 (s, 3H) 4.00-4.11 (m, 1 H) 6.44 (d, J=7.02 Hz, 1 H) 6.92 (dd, J=8.59, 2.54Hz, 1 H) 7.00 (dd, J=12.39, 2.44 Hz, 1 H) 7.42 (t, J=8.49 Hz, 1 H) 8.03(d, J=5.85 Hz, 1 H) 9.25 (br. s., 1 H) 11.10 (s, 1 H).

Example 28(2R)-4-[5-Fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (1.90 g, 98.8%) was obtained as a yellow solid from(4-methoxyphenyl)boronic acid (902 mg, 5.94 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (2.0 g, 3.87 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 495.4 (M−1).

Step B)(2R)-4-[5-Fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (651 mg, 41.3%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(1.90 g, 3.83 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamideExample 26, Step E. MS (LCMS) m/z 413.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.57 (s, 3 H) 2.08-2.23 (m, 1 H) 2.41-2.48 (m, 1 H) 3.11 (s, 3 H)3.72-3.80 (m, 1 H) 3.81 (s, 3 H) 3.97-4.13 (m, 1 H) 6.49 (d, J=7.81 Hz,1 H) 6.95-7.15 (m, 2 H) 7.46-7.67 (m, 2 H) 7.99 (d, J=6.63 Hz, 1 H) 9.24(s, 1 H) 11.11 (s, 1 H).

Example 29(2R)-4-[5-Fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) Ethyl(2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate

The title compound (484 mg) was obtained as a brown gum from(4-methylphenyl)boronic acid (229 mg, 1.68 mmol) and ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate,T2, (500 mg, 1.12 mmol) using a procedure analogous to that describedfor the preparation of ethyl(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate,Example 27, Step B. MS (LCMS) m/z 410.1 (M+1).

Step B)(2R)-4-[5-Fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

The title compound (294 mg, 65.2%) was obtained as a white solid fromethyl(2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate(484 mg, 1.18 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid, Example 26, Step C. MS (LCMS) m/z 382.0 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.14-2.25 (m, 0 H) 2.36 (s, 3 H) 2.43-2.54(m, 1 H) 3.17 (s, 3 H) 3.89-4.07 (m, 2 H) 6.46 (d, J=7.81 Hz, 1 H) 7.31(d, J=8.00 Hz, 2 H) 7.42-7.52 (m, 2 H) 8.03 (d, J=6.83 Hz, 1 H).

Step C)(2R)-4-[5-Fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (331 mg, 89.3%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (294 mg, 0.77 mmol) using a procedure analogous to that describedfor the preparation of2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 26, Step D. MS (LCMS) m/z 479.3 (M−1).

Step D)(2R)-4-[5-Fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (96 mg, 34%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(331 mg, 0.69 mmol) using a procedure analogous to that described forthe preparation of2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 397.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.58 (s, 3 H) 2.10-2.25 (m, 1 H) 2.37 (s, 3 H) 2.42-2.49 (m, 1 H)3.12 (s, 3 H) 3.71-3.84 (m, 1 H) 4.00-4.12 (m, 1 H) 6.51 (d, J=7.81 Hz,1 H) 7.32 (d, J=7.81 Hz, 2 H) 7.48 (dd, J=8.20, 1.76 Hz, 2 H) 8.02 (d,J=6.83 Hz, 1 H) 9.24 (d, J=1.76 Hz, 1 H) 11.11 (d, J=1.95 Hz, 1 H).

Example 30(2R)-4-{5-Fluoro-2-oxo-4-[4-(trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-{5-Fluoro-2-oxo-4-[4-(trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (69.7 mg, 49.1%) was obtained as a yellow-white solidfrom [4-(trifluoromethoxy)phenyl]boronic acid (82.3 mg, 0.47 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (133 mg, 0.26 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 20, Step A. MS (LCMS) m/z 551.1 (M−1).

Step B)(2R)-4-{5-Fluoro-2-oxo-4-[4-(trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (12.2 mg, 20.9%) was obtained as a white solid from(2R)-4-{5-fluoro-2-oxo-4-[4-(trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(68.9 mg, 0.13 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 467.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.57 (s, 3 H) 2.07-2.25 (m, 0 H) 2.39-2.55 (m, 1 H) 3.11 (s, 3 H)3.72-3.86 (m, 1 H) 3.97-4.13 (m, 1 H) 6.58 (d, 1 H) 7.50 (d, J=8.00 Hz,2 H) 7.65-7.77 (m, 2 H) 8.06 (d, J=6.44 Hz, 1 H) 9.23 (d, J=1.17 Hz, 1H) 11.08 (s, 1 H).

Example 31(2R)-4-[5-Fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (67 mg, 54%) was obtained as a white solid from(4-fluorophenyl)boronic acid (66.2 mg, 0.47 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (133 mg, 0.26 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 483.1 (M−1).

Step B)(2R)-4-[5-Fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (7.9 mg, 14%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(67 mg, 0.14 mmol) using a procedure analogous to that described for thepreparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 401.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.58 (s, 3 H) 2.10-2.24 (m, 1 H) 2.42-2.50 (m, 1 H) 3.12 (s, 3 H)3.71-3.88 (m, 1 H) 3.99-4.14 (m, 1 H) 6.55 (d, J=7.61 Hz, 1 H) 7.25-7.45(m, 2 H) 7.58-7.72 (m, 2 H) 8.05 (d, J=6.83 Hz, 1 H) 9.24 (s, 1 H) 11.10(s, 1 H).

Example 32(2R)-4-{5-Fluoro-4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)2-Methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine

The title compound (1.40 g) was obtained as a white solid from5-(4-bromophenyl)-2-methoxypyridine (1.0 g, 3.8 mmol) using a procedureanalogous to that described for the preparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole,Example 26, Step A. MS (LCMS) m/z 312.1 (M+1).

Step B)(2R)-4-{5-Fluoro-4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (273 mg, 61.4%) was obtained as a yellow solid from2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine(362 mg, 1.16 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (400 mg, 0.78 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 574.0 (M+1).

Step C)(2R)-4-{5-Fluoro-4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (156 mg, 67%) was obtained as a white solid from(2R)-4-{5-fluoro-4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(273 mg, 0.48 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 490.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.58 (s, 3 H) 2.09-2.27 (m, 0 H) 2.43-2.57 (m, 1 H) 3.12 (s, 3 H)3.73-3.86 (m, 1 H) 3.91 (s, 3 H) 4.00-4.14 (m, 1 H) 6.59 (d, J=7.61 Hz,1 H) 6.94 (d, J=8.59 Hz, 1 H) 7.60-7.73 (m, 2 H) 7.75-7.86 (m, 2 H)7.98-8.19 (m, 2 H) 8.57 (d, J=2.54 Hz, 1 H) 9.25 (br. S., 1 H) 11.10 (s,1 H).

Example 33(2R)-4-{4-[4-(Difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-{4-[4-(Difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (69.7 mg, 49.1%) was obtained as a yellow solid from2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(82.3 mg, 0.47 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (133 mg, 0.26 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 531.2 (M−1).

Step B)(2R)-4-{4-[4-(Difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (9.0 mg, 18%) was obtained as a white solid from(2R)-4-{4-[4-(difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(58.0 mg, 0.11 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 449.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)ppm 1.58 (s, 3 H) 2.09-2.26 (m, 1 H) 2.40-2.48 (m, 1 H) 3.12 (s, 3 H)3.71-3.86 (m, 1 H) 3.98-4.14 (m, 1 H) 6.55 (d, 1 H) 7.13-7.57 (m, 3 H)7.61-7.80 (m, 2 H) 8.05 (d, J=6.63 Hz, 1 H) 9.24 (d, J=1.76 Hz, 1 H)11.10 (d, J=1.56 Hz, 1 H).

Example 34(2R)-4-[5-Fluoro-4-(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (332.1 mg, 65.2%) was obtained as a yellow solid from(4-methoxy-3-methylphenyl)boronic acid (280 mg, 1.69 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (500 mg, 0.97 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 511.0 (M+1).

Step B)(2R)-4-[5-Fluoro-4-(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (46 mg, 17%) was obtained as a white solid from(2R)-4-[5-fluoro-4-(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(322 mg, 0.63 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 427.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.57 (s, 3 H) 2.08-2.25 (m, 4 H) 2.38-2.49 (m, 1 H) 3.11 (s, 3 H)3.70-3.81 (m, 1 H) 3.84 (s, 3 H) 3.97-4.11 (m, 1 H) 6.48 (d, 1 H) 7.05(d, J=8.39 Hz, 1 H) 7.28-7.50 (m, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.24(br. S., 1 H) 11.11 (s, 1 H).

Example 35(2R)-4-{4-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-{4-[4-(Difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (227 mg, 42.6%) was obtained as a yellow-white solidfrom2-[4-(difluoromethoxy)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(630 mg, 2.19 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (500 mg, 0.97 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 549.3 (M−1).

Step B)(2R)-4-{4-[4-(Difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (92 mg, 62%) was obtained as a white solid from(2R)-4-{4-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(227 mg, 0.41 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 467.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.57 (s, 3 H) 2.08-2.22 (m, 1 H) 2.40-2.48 (m, 1 H) 3.11 (s, 3 H)3.70-3.86 (m, 1 H) 3.97-4.14 (m, 1 H) 6.61 (d, 1 H) 7.09-7.38 (m, 1H)7.42-7.57 (m, 2 H) 7.69 (d, J=11.12 Hz, 1 H) 8.07 (d, J=6.63 Hz, 1 H)9.24 (br. S., 1 H) 11.08 (s, 1 H).

Example 36(2R)-4-{5-Fluoro-4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) (1E,2E)-Ethanedial bis[(4-bromo-2-fluorophenyl)hydrazone]

(4-Bromo-3-fluorophenyl)hydrazine-hydrochloride (5.0 g, 24.3 mmol) wasadded to a mixture of EtOAc (60 mL) and 3 N aq NaOH (60 mL) and themixture was stirred until all solids went into solution. The organiclayer was separated and the aqueous layer was extracted with EtOAc (2×60mL). The combined organics were washed with brine (60 mL), dried(MgSO₄), filtered and concentrated to afford an orange solid (3.27 g,15.9 mmol). The solid was suspended in toluene (25 mL). Oxalaldehyde(40% aq solution, 912 uL, 7.92 mmol) was added dropwise to the solutionand the reaction was stirred overnight at rt. The precipitate wascollected via filtration and washed with toluene (25 mL) and hexanes (50mL). The solid was dried under vacuum to afford the title compound as ayellow solid (2.61 g, 78.1%). MS (LCMS) m/z 431.1 (M−1).

Step B) 2-(4-Bromo-2-fluorophenyl)-2H-1,2,3-triazole

Copper (II) trifluoromethanesulfonate (218 mg, 0.60 mmol) was added to aslurry of (1E,2E)-ethanedial bis[(4-bromo-2-fluorophenyl)hydrazone](2.61g, 6.04 mmol) in toluene (25 mL). The reaction was heated to reflux andstirred at this temperature overnight. The reaction was allowed to cooland was filtered through celite, and the filter pad was washed withEtOAc (100 mL). The combined filtrates were washed with 1 N aq HCl(3×100 mL), water (100 mL), and brine (100 mL) and then dried (MgSO₄),filtered and concentrated. The crude product was purified via flashchromatography using a Varian SF25-40 g column and an eluent of EtOAc inhexanes (0-50%) to afford the title compound as a yellow solid (1.08 g,73.9%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (ddd, 1 H) 7.47-7.54(m, 1 H) 7.76 (t, 1 H) 7.90 (s, 2 H).

Step C)2-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole

The title compound (1.54 g) was obtained as a yellow solid from2-(4-bromo-2-fluorophenyl)-2H-1,2,3-triazole (1.08 g, 4.82 mmol) using aprocedure analogous to that described for the preparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole,Example 26, Step A. MS (LCMS) m/z 290.1 (M+1).

Step D)(2R)-4-{5-Fluoro-4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (275 mg, 51.5%) was obtained as a yellow solid from2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole(420 mg, 1.45 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (500 mg, 0.97 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 550.3 (M−1).

Step E)(2R)-4-{5-Fluoro-4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (133 mg, 57%) was obtained as a white solid from(2R)-4-{5-fluoro-4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(275 mg, 0.50 mmol) through a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 468.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.58 (s, 3 H) 2.10-2.25 (m, 0 H) 2.43-2.56 (m, 1 H) 3.12 (s, 3 H)3.74-3.89 (m, 1 H) 4.00-4.15 (m, 1 H) 6.70 (d, J=7.61 Hz, 1 H) 7.60-7.66(m, 1 H) 7.75-7.86 (m, 1 H) 8.00 (t, J=8.20 Hz, 1 H) 8.10 (d, J=6.63 Hz,1 H) 8.23 (s, 2 H) 9.24 (br. S., 1 H) 11.08 (s, 1 H).

Example 37(2R)-4-{5-Fluoro-4-[3-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) (1E,2E)-Ethanedial bis[(4-bromo-2-methylphenyl)hydrazone]

The title compound (1.45 g, 87.9%) was obtained as a yellow solid from(4-bromo-2-methylphenyl)hydrazine-hydrochloride (2.00 g, 8.42 mmol) andoxalaldehyde (40% aq solution, 450 uL, 3.9 mmol) through a procedureanalogous to that described for the preparation of (1E,2E)-ethanedialbis[(4-bromo-2-fluorophenyl)hydrazone], Example 36, Step A. MS (LCMS)m/z 425.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 6 H) 7.09-7.33(m, 6 H) 7.95 (s, 2 H) 9.73 (s, 2 H).

Step B) 2-(4-Bromo-2-methylphenyl)-2H-1,2,3-triazole

The title compound (608 g, 59.0%) was obtained as a yellow solid from(1E,2E)-ethanedial bis[(4-bromo-2-methylphenyl)hydrazone (1.45 g, 3.42mmol) through a procedure analogous to that described for thepreparation of 2-(4-bromo-2-fluorophenyl)-2H-1,2,3-triazole, Example 36,Step B. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.38 (s, 3 H) 7.44-7.48 (m,2 H) 7.50-7.53 (m, 1 H) 7.85 (s, 2 H).

Step C)2-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole

The title compound (688 mg, 82.3%) was obtained as an orange solid from2-(4-bromo-2-methylphenyl)-2H-1,2,3-triazole (698 mg, 2.93 mmol) througha procedure analogous to that described for the preparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole,Example 26, Step A. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.41 (m,12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz, 1 H) 7.76 (d, J=7.81 Hz, 1 H)7.80 (s, 1 H) 7.85 (s, 2 H).

Step D)(2R)-4-{5-Fluoro-4-[3-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (630 mg, 71.5%) was obtained as a yellow solid from2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole(688 mg, 2.41 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (830 mg, 1.61 mmol) through a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 546.2 (M−1).

Step E)(2R)-4-{5-Fluoro-4-[3-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (253 mg, 47.5%) was obtained as a white solid from(2R)-4-{5-fluoro-4-[3-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(630 mg, 1.15 mmol) through a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 464.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.58 (s, 3 H) 2.11-2.26 (m, 1 H) 2.39 (s, 3 H) 3.11 (s, 3 H)3.74-3.87 (m, 1 H) 3.99-4.16 (m, 1 H) 6.64 (d, J=7.61 Hz, 1 H) 7.60 (d,J=8.00 Hz, 1 H) 7.63-7.77 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.16 (s, 2H) 9.24 (br. s., 1 H) 11.09 (s, 1 H).

Example 38(2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) 3,5-Difluoro-4-iodopyridin-2(1 H)-one

2,3,5-Trifluoro-4-iodopyridine (6.03 g, 23.3 mmol) was suspended in 6 Maq HCl (250 mL). The mixture was heated to reflux and was stirred atthis temperature overnight. The reaction was concentrated to dryness toafford the title compound as an orange solid (4.14 g, 69.2%). MS (LCMS)m/z 257.9 (M+1).

Step B) Ethyl(2R)-4-(3,5-difluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the3,5-difluoro-4-iodopyridin-2(1 H)-one (1.0 g, 3.9 mmol) and ethyl(2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, T1, (1.45 g, 5.06mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The resultingsuspension was heated to reflux and was stirred at this temperature for72 h. The reaction was filtered through celite, and the filter pad waswashed with EtOAc (3×50 mL). The combined filtrates were concentratedand the crude product was purified via flash chromatography on anAnalogix SF15-24 g column using an eluent of EtOAc in hexanes (0-50%) toafford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS)m/z 463.9 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 3 H) 1.58 (s,3 H) 2.20 (dt, J=13.90, 7.00 Hz, 1 H) 2.52-2.62 (m, 1 H) 3.14 (s, 3 H)4.00 (t, J=7.61 Hz, 2 H) 4.05-4.22 (m, 2 H) 7.94 (dd, J=4.20, 2.05 Hz, 1H).

Step C) Ethyl(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

The title compound (110 mg, 63%) was obtained as a white solid fromphenylboronic acid (98.8 mg, 0.81 mmol) and ethyl(2R)-4-(3,5-difluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(250 mg, 0.54 mmol) using a procedure analogous to that described forthe preparation of ethyl(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate,Example 26, Step B. MS (LCMS) m/z 414.0 (M+1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.33-1.46 (m, 3 H) 1.78 (s, 3 H) 2.44-2.65 (m, 2 H)3.14 (s, 3 H) 3.98-4.16 (m, 1 H) 4.25-4.43 (m, 3 H) 7.23 (dd, J=5.07,2.15 Hz, 1 H) 7.40-7.61 (m, 5 H).

Step D)(2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid

The title compound (91 mg, 79.2%) was obtained as a white solid fromethyl(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(110 mg, 0.27 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid, Example 26, Step C. MS (LCMS) m/z 386.0 (M+1).

Step E)(2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (75.9 mg, 66%) was obtained as an off-white solidfrom(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid (91 mg, 0.36 mmol) using a procedure analogous to that describedfor the preparation of2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 26, Step D. MS (LCMS) m/z 483.2 (M+1).

Step F)(2R)-4-(3,5-Difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (13.9 mg, 22%) was obtained as a white solid from(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(75 mg, 0.16 mmol) using a procedure analogous to that described for thepreparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamideExample 26, Step E. MS (LCMS) m/z 401.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.59 (s, 3 H) 2.11-2.22 (m, 1 H) 2.52-2.62 (m, 1 H) 3.10 (s, 3 H)3.79-3.99 (m, 1 H) 4.03-4.20 (m, 1 H) 7.40-7.64 (m, 5 H) 7.98 (dd,J=5.85, 1.95 Hz, 1 H) 9.24 (br. S., 1 H) 11.01 (s, 1 H).

Example 39(2R)-4-(5-Fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-(5-Fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid

Potassium hydroxide (100 mg, 1.78 mmol) was added to a solution of ethyl(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(77 mg, 0.19 mmol) in tetrahydrofuran:methanol:water (2:2:1 10 mL). Thesolution was heated to 50° C. and stirred at this temperature for 4 h.The reaction was concentrated and the residue was dissolved in 1 N aqNaOH (50 mL). The aqueous layer was washed with EtOAc (3×50 mL) andacidified to a pH of 3 using concentrated HCl. The solid was collectedvia filtration and was washed with water (30 mL) and hexanes (30 mL) toafford the title compound as a white solid (70 mg, 95%). MS (LCMS) m/z398.0 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) ppm 1.69-1.79 (m, 3 H)2.30-2.46 (m, 1 H) 2.55-2.72 (m, 1 H) 3.18 (s, 3 H) 3.66 (s, 3 H)4.08-4.22 (m, 1 H) 4.23-4.38 (m, 1 H) 7.39-7.51 (m, 5 H) 7.60 (d, 1 H).

Step B)(2R)-4-(5-Fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (52 mg, 83%) was obtained as an off-white solid from(2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoicacid (50 mg, 0.13 mmol) using a procedure analogous to that describedfor the preparation of2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 26, Step D. MS (LCMS) m/z 497.0 (M+1).

Step C)(2R)-4-(5-Fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (20.2 mg, 48%) was obtained as an off-white solidfrom(2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(75 mg, 0.16 mmol) using a procedure analogous to that described for thepreparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 413.0 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.72 (s, 3 H) 2.30-2.50 (m, 1 H) 2.55-2.78 (m, 1 H)3.10 (s, 3 H) 3.68 (s, 3 H) 3.95-4.06 (m, 1 H) 4.21-4.37 (m, 1 H)7.37-7.55 (m, 5 H) 7.61 (d, 1 H).

Example 40(2R)-4-(5-Fluoro-3-hydroxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-(5-Fluoro-3-hydroxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Boron tribromide (760 μL, 0.76 mmol, 1.0 M in dichloromethane) was addedto a solution of(2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide(156 mg, 0.378 mmol) in DCM (16.0 mL) at 0° C. The reaction was allowedto warm to rt and stirred overnight. The reaction mixture wasconcentrated to afford a brown solid. The crude product was purified viaprepratory HPLC to afford the title compound as a yellow solid (25.4 mg,16.9%). MS (LCMS) m/z 399.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59(s, 3 H) 2.11-2.25 (m, 1 H) 3.07 (s, 1 H) 3.13 (s, 2 H) 3.70-3.88 (m, 1H) 4.02-4.26 (m, 1 H) 7.11 (d, J=7.81 Hz, 1 H) 7.37-7.65 (m, 5 H).

Example 41(2R)-4-[5-Fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole

The title compound (730 mg, 67.0%) was obtained as a white solid from3-(4-bromophenyl)isoxazole (900 mg, 4.02 mmol) using a procedureanalogous to that described for the preparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole,Example 26, Step A. MS (APCI) m/z 272.1 (M+1). ¹H NMR (400 MHz,CHLOROFORM-d) ppm 1.36-1.41 (m, 12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz,1 H) 7.76 (d, J=7.81 Hz, 1 H) 7.80 (s, 1 H) 7.85 (s, 2 H). ¹H NMR (400MHz, CHLOROFORM-d) ppm 1.35 (s, 12 H) 6.66-6.70 (m, 1 H) 7.83 (s, 2 H)7.88 (s, 2 H) 8.42-8.48 (m, 1 H).

Step B)(2R)-4-[5-Fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (655 mg, 63.4%) was obtained as a colorless oil from3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole (525mg, 1.94 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (1.00 g, 1.94 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (APCI) m/z 532.3 (M−1). ¹H NMR (400 MHz,CHLOROFORM-d) ppm 1.53-1.97 (m, 9 H) 2.31-2.47 (m, 1 H) 2.47-2.60 (m, 1H) 3.19 (d, J=2.54 Hz, 3 H) 3.53-3.74 (m, 1 H) 4.00 (br. s., 1 H) 4.12(s, 1 H) 4.27-4.40 (m, 1 H) 5.15 (d, J=14.24 Hz, 1 H) 6.63-6.75 (m, 2 H)7.42 (d, J=5.46 Hz, 1 H) 7.62 (d, J=8.00 Hz, 2 H) 7.92 (d, J=8.59 Hz, 2H) 8.49 (d, J=1.56 Hz, 1 H) 11.85 (d, J=17.76 Hz, 1 H).

Step C)(2R)-4-[5-Fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

A solution of 1.0 M aq HCl (15 mL) was added slowly to a solution of(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(655 mg, 1.23 mmol) in 1,4-dioxane (30 mL) at rt. The reaction wasallowed to stir at rt overnight. The reaction was concentrated to acrude material. Water (30 mL) was added to the crude material and themixture was boiled for 5 minutes. The mixture was allowed to cool to rtand the solid that formed was collected via filtration and dried underhigh vacuum to afford the title compound as a light yellow solid (314mg, 56.9%). MS (APCI) m/z 450.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.55 (s, 3 H) 2.10-2.21 (m, 1 H) 2.42-2.49 (m, 1 H) 3.09 (s, 3 H)3.66-3.85 (m, 1 H) 3.96-4.09 (m, 1 H) 6.59 (d, J=7.61 Hz, 1 H) 7.21 (d,J=1.56 Hz, 1 H) 7.71 (dd, J=8.39, 1.76 Hz, 2 H) 8.00 (d, J=8.39 Hz, 2 H)8.04 (d, J=6.44 Hz, 1 H) 9.03 (d, J=1.56 Hz, 1 H) 9.16-9.28 (m, 1 H)11.06 (s, 1 H).

Example 42(2R)-4-{5-Fluoro-4-[4-(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazole

The title compound (240 mg, 34.3%) was obtained as a white solid from2-(4-iodophenyl)-1,3-oxazole (700 mg, 2.58 mmol) using a procedureanalogous to that described for the preparation of2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole,Example 26, Step A. MS (APCI) m/z 272.2 (M+1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.35 (s, 12 H) 7.23-7.24 (m, 1 H) 7.69-7.73 (m, 1 H)7.86-7.91 (m, 2 H) 7.98-8.05 (m, 2 H).

Step B)(2R)-4-{5-Fluoro-4-[4-(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (145 mg, 30.7%) was obtained as a colorless oil from2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazole(240 mg, 0.89 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (435 mg, 0.84 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (APCI) m/z 532.5 (M−1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.52-1.98 (m, 9 H) 2.35-2.47 (m, 1 H) 2.48-2.60 (m,1 H) 3.20 (d, J=2.93 Hz, 3 H) 3.56-3.71 (m, 1 H) 3.96-4.07 (m, 1 H)4.12-4.22 (m, 1 H) 4.32-4.46 (m, 1 H) 5.12-5.23 (m, 1 H) 6.69-6.75 (m, 1H) 7.27 (s, 1 H) 7.37-7.45 (m, 1 H) 7.63 (dd, J=8.39, 1.56 Hz, 2 H) 7.75(s, 1 H) 8.14 (d, J=8.39 Hz, 2 H) 11.79-11.95 (m, 1 H).

Step C)(2R)-4-{5-Fluoro-4-[4-(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (31 mg, 25%) was obtained as a solid from(2R)-4-{5-fluoro-4-[4-(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(145 mg, 0.27 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 41, Step C. MS (APCI) m/z 450.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.55 (s, 3 H) 2.11-2.23 (m, 1 H) 2.39-2.47 (m, 1 H) 3.09 (s, 3 H)3.61-3.84 (m, 1 H) 3.91-4.12 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.41 (s,1 H) 7.72 (d, J=7.02 Hz, 2 H) 7.91-8.12 (m, 3 H) 8.25 (s, 1 H) 9.12-9.29(m, 1 H) 10.87-11.17 (m, 1 H).

Example 43(2R)-4-[5-Fluoro-4-(4-trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (216 mg, 76.9%) was obtained as a light orange oilfrom (4-trideuteromethylphenyl)boronic acid (85 mg, 0.61 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (300 mg, 0.58 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (APCI) m/z 482.4 (M−1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.50-1.97 (m, 9 H) 2.32-2.44 (m, 1 H) 2.44-2.59 (m,1 H) 3.17 (d, J=2.34 Hz, 3 H) 3.53-3.69 (m, 1 H) 4.00 (br. s., 1 H)4.10-4.20 (m, 1 H) 4.31 (br. s., 1 H) 5.14 (d, J=14.44 Hz, 1 H) 6.65(dd, J=7.22, 1.56 Hz, 1 H) 7.21-7.28 (m, 2 H) 7.36 (d, J=5.27 Hz, 1 H)7.38-7.44 (m, 2 H) 11.89-12.06 (m, 1 H).

Step B)(2R)-4-[5-Fluoro-4-(4-trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (62 mg, 35%) was obtained as a solid from(2R)-4-[5-fluoro-4-(4-trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(145 mg, 0.27 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 41, Step C. MS (APCI) m/z 400.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.14 (br. s., 1 H) 2.47 (br. s., 1 H) 3.08 (s, 3 H)3.75 (br. s., 1 H) 4.02 (br. s., 1 H) 6.47 (d, J=7.61 Hz, 1 H) 7.28 (d,J=8.00 Hz, 2 H) 7.44 (d, J=7.02 Hz, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.21(s, 1 H) 11.07 (s, 1 H).

Example 44(2R)-4-[5-Fluoro-4-(4-trideuteromethoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[5-Fluoro-4-(4-trideuteromethoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (216 mg, 76.9%) was obtained as a colorless oil from(4-trideuteromethoxyphenyl)boronic acid (120 mg, 0.78 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (400 mg, 0.78 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. (122 mg, 31.5%). MS (APCI) m/z 498.3 (M−1). ¹H NMR(400 MHz, CHLOROFORM-d) ppm 1.49-1.98 (m, 9 H) 2.38 (dd, J=7.12, 3.80Hz, 1 H) 2.44-2.61 (m, 1 H) 3.18 (d, J=2.54 Hz, 3 H) 3.65 (d, J=11.51Hz, 1 H) 3.89-4.04 (m, 1 H) 4.11-4.22 (m, 1 H) 4.24-4.38 (m, 1 H) 5.15(d, J=14.63 Hz, 1 H) 6.64 (dd, J=7.41, 1.37 Hz, 1 H) 6.96 (d, J=8.78 Hz,2 H) 7.35 (d, J=5.66 Hz, 1 H) 7.43-7.51 (m, 2 H) 12.02 (d, J=15.02 Hz, 1H).

Step B)(2R)-4-[5-fluoro-4-(4-trideuteromethoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (55 mg, 55%) was obtained as a solid from(2R)-4-[5-fluoro-4-(4-trideuteromethoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(120 mg, 0.24 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 41, Step C. MS (APCI) m/z 416.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 2.14 (br. s., 1 H) 2.47 (br. s., 1 H) 3.08 (s, 3 H)3.74 (br. s., 1 H) 4.02 (br. s., 1 H) 6.46 (d, J=7.81 Hz, 1 H) 7.02 (d,J=8.39 Hz, 2 H) 7.51 (d, J=7.41 Hz, 2 H) 7.96 (d, J=6.63 Hz, 1 H) 9.20(s, 1 H) 11.07 (s, 1 H).

Example 45(2R)-4-[4-(4-Pentadeuteroethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(4-Pentadeuteroethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (184 mg 46.0%) was obtained as a colorless oil from(4-pentadeuteroethoxyphenyl)boronic acid (132 mg, 0.78 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (400 mg, 0.78 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (APCI) m/z 514.4 (M−1). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.53-1.97 (m, 9 H) 2.39 (dt, J=7.27, 3.68 Hz, 1 H)2.45-2.60 (m, 1 H) 3.19 (d, J=2.73 Hz, 3 H) 3.65 (d, J=11.51 Hz, 1 H)3.90-4.04 (m, 1 H) 4.16 (dd, J=11.22, 2.44 Hz, 1 H) 4.24-4.38 (m, 1 H)5.16 (d, J=14.83 Hz, 1 H) 6.64 (dd, J=7.42, 1.17 Hz, 1 H) 6.95 (d,J=8.59 Hz, 2 H) 7.34 (d, J=5.66 Hz, 1 H) 7.40-7.52 (m, 2 H) 12.03 (br.s., 1 H).

Step B)(2R)-4-[4-(4-Pentadeuteroethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (152 mg, 98.7%) was obtained as an off-white solidfrom(2R)-4-[4-(4-pentadeuteroethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(120 mg, 0.24 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 41, Step C. MS (APCI) m/z 432.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.54 (s, 3 H) 1.89-2.22 (m, 1 H) 2.32-2.47 (m, 1 H) 2.92-3.15 (m,3 H) 3.57-3.80 (m, 1 H) 4.01 (br. s., 1 H) 6.45 (d, J=7.81 Hz, 1 H) 7.01(d, J=8.78 Hz, 2 H) 7.50 (d, J=7.22 Hz, 2 H) 7.96 (d, J=6.83 Hz, 1 H)9.21 (br. s., 1 H) 11.08 (s, 1 H).

Example 46(2R)-4-{4-[4-(Cyclopropyloxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)2-[4-(Cyclopropyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Pd(dppf)Cl₂ (770 mg, 0.94 mmol) was added to a degassed suspension of1-bromo-4-(cyclopropyloxy)benzene (2.0 g, 9.39 mmol), potassium acetate(2.76 g, 28.12 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.62 g,10.32 mmol) in anhydrous DMSO (20 mL). The reaction was heated to 80° C.and stirred at this temperature for 5 h. The reaction was allowed tocool to rt and diluted with water and diethyl ether. The organic phasewas separated and the aqueous phase was extracted with diethyl ether.The organics were combined, dried (MgSO₄), filtered, and concentrated invacuo. Hexanes were added to the residue and the resulting yellowsolution was decanted from the brown residue. The yellow solution wasconcentrated, and the residue was purified via column chromatographyusing an eluent of 2% ethyl acetate in hexanes to afford title compoundas a colorless oil (878 mg, 36%). MS (LCMS) m/z 261.2 (M+1). ¹H NMR (400MHz, CHLOROFORM-d) ppm 0.74-0.83 (m, 4 H) 1.34 (s, 12 H) 3.73-3.82 (m, 1H) 7.05 (d, 2 H) 7.75 (d, 2 H).

Step B)(2R)-4-{4-[4-(Cyclopropyloxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (560 mg 55.3%) was obtained as a colorless oil from2-[4-(cyclopropyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(554 mg, 2.13 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (1.0 g, 1.94 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (APCI) m/z 521.4 (M−1). ¹H NMR (400 MHz,CHLOROFORM-d) ppm 0.57-0.82 (m, 4 H) 1.42-1.91 (m, 9 H) 2.27-2.41 (m, 1H) 2.41-2.58 (m, 1 H) 3.13 (s, 4 H) 3.45-3.64 (m, 1 H) 3.72 (dd, J=5.46,2.93 Hz, 1 H) 3.80-3.98 (m, 1 H) 4.12 (d, J=10.93 Hz, 1 H) 4.17-4.31 (m,1 H) 5.11 (d, J=13.85 Hz, 1 H) 6.59 (d, J=7.41 Hz, 1 H) 6.97-7.13 (m, 2H) 7.36 (d, J=5.46 Hz, 1 H) 7.43 (d, J=8.59 Hz, 2 H) 11.82-12.08 (m, 1H).

Step B)(R)-4-(4-(4-Cyclopropoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (280 mg, 59.6%) was obtained as an off-white solidfrom(2R)-4-(4-(4-cyclopropoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(560 mg, 1.07 mmol) using a procedure analogous to that described forthe preparation of(R)-4-(5-fluoro-4-(4-(isoxazol-3-yl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 41, Step C. MS (APCI) m/z 439.0 (M+1). ¹H NMR (400 MHz,DMSO-d₆)™ ppm 0.55-0.69 (m, 2 H) 0.74-0.85 (m, 2 H) 1.54 (s, 3 H)2.03-2.26 (m, 1 H) 2.33-2.46 (m, 1 H) 3.08 (s, 3 H) 3.64-3.80 (m, 1 H)3.88 (dt, J=6.05, 3.02 Hz, 1 H) 3.94-4.10 (m, 1 H) 6.46 (d, J=7.81 Hz, 1H) 7.02-7.23 (m, 2 H) 7.52 (dd, J=8.78, 1.95 Hz, 2H) 7.97 (d, J=6.63 Hz,1 H) 9.21 (s, 1 H) 11.08 (s, 1 H).

Example 47(2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A)(2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (560 mg 55.3%) was obtained as a colorless oil from(2,2-difluoro-1,3-benzodioxol-5-yl)boronic acid (129 mg, 0.639 mmol) and(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,T3, (300 g, 0.581 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 19, Step A. MS (LCMS) m/z 545.3 (M−1).

Step B)(2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Aqueous HCl (1.42 mL, 1.42 mmol) was added to a solution of(2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(259 mg, 0.474 mmol) in ethanol (5 mL) and water (2 mL) and the reactionwas stirred overnight at rt. The solid was collected via filtration,washed with water (5×3 mL) and dried under reduced pressure to affordthe title compound (143 mg, 65.3%). ¹H NMR (400 MHz, DMSO-d₆) d ppm 1.58(s, 3 H) 2.07-2.24 (m, 1 H) 2.36-2.49 (m, 1 H) 3.11 (s, 3 H) 3.68-3.86(m, 1 H) 3.98-4.13 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.36-7.49 (m, 1 H)7.55 (d, J=8.39 Hz, 1 H) 7.68 (s, 1 H) 8.06 (d, J=6.63 Hz, 1 H) 9.24(br. s., 1 H) 11.08 (s, 1 H).

Example 48(2R)-4-[5-Fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) Ethyl(2R)-4-[5-fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate

A solution of ethyl(2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate(500 mg, 1.12 mmol) and diisopropylethylamine (6.0 mL, 30 mmol) intetrahydrofuran (15 mL) was degassed with nitrogen. Pd(PPh₃)₄ (65.4 mg,0.056) and copper iodide (21.8 mg, 0.112 mmol) were added to thesolution, followed by phenylacetylene (150 uL, 1.4 mmol). The reactionwas allowed to stir until complete via TLC. The reaction was dilutedwith EtOAc (100 mL) and washed with saturated aq NH₄Cl (100 mL) andbrine (100 mL), dried (MgSO₄), filtered, and concentrated. The cruderesidue was purified via flash chromatography using a Varian SF15-24 gcolumn and an eluent of EtOAc in hexanes (30-80%) to afford the titlecompound as a yellow solid (389 mg, 82.6%). MS (LCMS) m/z 420.0 (M+1).¹H NMR (400 MHz, CHLOROFORM-d) ppm 1.35 (t, 3 H) 1.75 (s, 3 H) 2.42-2.61(m, 2 H) 3.11 (s, 3 H) 3.91-4.00 (m, 1 H) 4.19-4.27 (m, 1 H) 4.30 (q,J=7.02 Hz, 2 H) 6.72 (d, J=6.63 Hz, 1 H) 7.27 (t, J=2.34 Hz, 2 H)7.35-7.44 (m, 2 H) 7.55-7.60 (m, 2 H).

Step B)(2R)-4-[5-Fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid

The title compound (195.1 mg, 72.1%) was obtained as a white solid fromethyl(2R)-4-[5-fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate(290 mg, 0.52 mmol) using a procedure analogous to that described forthe preparation of ethyl(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate,Example 26, Step C. MS (LCMS) m/z 392.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)ppm 1.55 (s, 3 H) 2.10-2.24 (m, 0 H) 2.40-2.56 (m, 1 H) 3.16 (s, 3 H)3.87-4.06 (m, 2 H) 6.65 (d, J=6.83 Hz, 1 H) 7.43-7.55 (m, 3 H) 7.57-7.65(m, 2 H) 8.07 (d, J=5.46 Hz, 1 H).

Step C)(2R)-4-[5-Fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (232 mg, 95.0%) was obtained as a white solid from(2R)-4-[5-fluoro-2-oxo-4-(phenylethynyl)89yridine-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoicacid (195.1 mg, 0.50 mmol) using a procedure analogous to that describedfor the preparation of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamideExample 26, Step D.

Step D)(2R)-4-[5-Fluoro-2-oxo-4-(phenylethynyl)90yridine-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (124.4 mg, 64.7%) was obtained as a white solid from(2R)-4-[5-fluoro-2-oxo-4-(phenylethynyl)90yridine-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(232 mg, 0.47 mmol) using a procedure analogous to that described forthe preparation of(2R)-4-{5-Fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 407.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.56 (s, 3 H) 2.04-2.21 (m, 1 H) 2.37-2.49 (m, 1 H) 3.10 (s, 3 H)3.69-3.85 (m, 1 H) 3.92-4.12 (m, 1 H) 6.69 (d, 1 H) 7.39-7.57 (m, 3 H)7.57-7.68 (m, 2 H) 8.05 (d, J=5.46 Hz, 1 H) 9.22 (s, 1 H) 11.04 (s, 1H).

Example 49(2R)-4-{5-Fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Step A) 2-(3-Iodophenoxy)-1,3-thiazole

Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole(1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrousDMF (30 mL). The reaction was heated to 135° C. and stirred at thistemperature overnight. The reaction was allowed to cool, then was pouredinto water (100 mL), and extracted with EtOAc (3×100 mL). The combinedorganics were washed with brine (100 mL), dried (MgSO₄), filtered, andconcentrated. The crude product was purified via flash chromatographyusing a Varian SF15-24 g column and an eluent of EtOAc in hexanes(0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS(LCMS) m/z 304.1 (M+1).

Step B)2-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1,3-thiazole

The title compound (1.33 g) was prepared as a crude brown solid from2-(3-iodophenoxy)-1,3-thiazole (500 mg, 1.65 mmol) using a procedureanalogous to that described for2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole,Example 1, Step A. MS (LCMS) m/z 304.0 (M+1).

Step C) Ethyl(2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate

The title compound (534 mg) was prepared as a crude brown oil from2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1,3-thiazole(1.33 g, 4.39 mmol) and T2 (400 mg, 0.90 mmol) using a procedureanalogous to that described for ethyl(2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate,Example 18, Step D. MS (LCMS) m/z 495.2 (M+1).

Step D)(2R)-4-{5-Fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid

The title compound (144 mg, 28.4%) was prepared as an off-white solidfrom ethyl(2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate(538 mg, 1.09 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid, Example 26, Step C. MS (LCMS) m/z 467.1 (M+1). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.57 (s, 3 H) 2.12-2.27 (m, 1 H) 3.17 (s, 3 H) 3.85-4.11(m, 2 H) 6.55 (d, J=7.61 Hz, 1 H) 7.24-7.35 (m, 2 H) 7.44-7.66 (m, 4 H)8.07 (d, J=6.44 Hz, 1 H).

Step E)(2R)-4-{5-Fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

The title compound (115 mg, 65.8%) was prepared as an off-white solidfrom(2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoicacid (144 mg, 0.31 mmol) using a procedure analogous to that describedfor(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide,Example 26, Step D. MS (LCMS) m/z 566.2 (M−1).

Step F)(2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

The title compound (66.8 mg, 68.4%) was prepared as a white solid from(2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide(115 mg, 0.20 mmol) using a procedure analogous to that described for(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide,Example 26, Step E. MS (LCMS) m/z 482.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.57 (s, 3 H) 2.09-2.23 (m, 1 H) 3.11 (s, 3 H) 3.70-3.87 (m, 1 H)3.97-4.14 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.25-7.35 (m, 2 H) 7.45-7.67(m, 4 H) 8.06 (d, J=6.44 Hz, 1 H) 9.23 (s, 1 H) 11.08 (s, 1 H).

Biological Examples

In order to assess the compounds biological activity, selected in vitroassays were conducted on selected compounds. One of the assays measuredthe compounds ability to disrupt the synthesis of lipopolysaccharide,LPS, which is a component of the outer membrane of Gram-negativebacteria. Disruption of this synthesis is lethal to the bacteria. Theassay determined the compound's ability to inhibit LpxC, which is thefirst enzyme in the biosynthetic pathway for LPS (measured as IC₅₀).Additionally, MICs (minimal inhibitory concentrations) were determinedfor several bacteria. The specific protocols are described below:

A) IC₅₀ Assay, LpxC Enzyme from P. aeruginosa (Labeled as PA LpxC EnzymeIC₅₀):

IC₅₀ determination in the LpxC enzyme assay was carried out in a similarmanner to that described by Malikzay et al in the 2006 Poster, ScreeningLpxC (UDP-3-O—(R-3-hydroxymyristoyl)-GlcNAc deacetylase) using BioTroveRapidFire HTS Mass Spectrometry (aNew Lead Discovery and bInflammationand Infectious Disease, cStructural Chemistry, Schering-Plough ResearchInstitute, Kenilworth, N.J. 07033, (BioTrove, Inc. 12 Gill St., Suite4000, Woburn, Mass. 01801). Briefly, Pseudomonas aeruginosa LpxC enzyme(0.1 nM) purified from E. coli-overexpressing bacteria was incubated at25° C. in a final volume of 50 ul containing 0.5 uMUDP-3-O—(R-3-hydroxydecanoyl)-N-acetylglucosamine, 1 mg/mL BSA, and 50mM sodium phosphate buffer, pH 8.0 in the presence and absence ofinhibitor compound. At the end of 1 hour, 5 ul of 1 N HCl was added tostop the enzyme reaction, the plates were centrifuged, and thenprocessed with the BioTrove Rapidfire HTMS Mass Spectrometry System. Ano-enzyme control was used in calculating the IC₅₀ values from thepercent conversion values.

B) MIC Determinations: The in vitro antibacterial activity of compoundsdescribed in the Examples was evaluated by minimum inhibitoryconcentration (MIC) testing according to Clinical and LaboratoryStandards Institute (CLSI). See: Clinical and Laboratory StandardsInstitute. Methods for Dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically; Approved Standard-Eighth Edition. CLSIdocument M7-A8 [ISBN 1-56238-689-1]. Clinical and Laboratory StandardsInstitute, 940 West Valley Road, Suite 1400, Wayne, Pa. 19087-1898 USA,2006; also Clinical and Laboratory Standards Institute. PerformanceStandards for Antimicrobial Susceptibility Testing; TwentiethInformational Supplement. CLSI document M100-S20 [ISBN1-56238-716-2].Clinical and Laboratory Standards Institute.

The MIC determination is a standard laboratory method for evaluating theantibacterial activity of a compound. The MIC represents the lowest drugconcentration that inhibits visible growth of bacteria followingovernight incubation. In order to determine the MIC value, a range ofdrug concentrations (e.g. 0.06 μg/mL to 64 μg/mL) are incubated with adefined strain of bacteria. Typically, the drug concentration range isbroken down into 2-fold increments (e.g. 0.06 μg/mL, 0.12 μg/mL. 0.25μg/mL, 0.50 μg/mL, 1.0 μg/mL, etc.) and the various drug concentrationsare all individually incubated overnight with approximately the samenumber of bacteria. The MIC is then determined by visually inspectingthe drug effect at each concentration, and identifying the lowest drugconcentration that has inhibited bacterial growth as compared to thedrug free control. Typically, bacteria continue to grow at drugconcentrations lower than the MIC and don't grow at concentrations atand above the MIC.

The MIC values described in Table 2 and 3 below were derived from assayswherein each test compound was evaluated in duplicate. In cases wherethe duplicate values varied by 0-2-fold, the lower of the two values wasreported below. Generally speaking, if the duplicate values varied bymore than 2-fold, the assay was considered non-valid and was repeateduntil the variation between duplicate runs was ≦2-fold. In line with theCLSI guidelines referred to above, both control organisms and referencecompounds were utilized in each MIC assay to provide proper qualitycontrol. MIC values generated with these control organisms and referencecompounds were required to fall within a defined range for the assay tobe considered valid and be included herein. Those skilled in the artwill recognize that MIC values can and do vary from experiment toexperiment. Generally speaking, it should be recognized that MIC valuesoften vary +/−2-fold from experiment to experiment. While a single MICis reported for each compound and each microorganism, the reader shouldnot conclude that each compound was only tested once. Several of thecompounds were subjected to multiple tests. The data reported in Tables2 and 3 is reflective of the compounds relative activity and differentMICs may have been generated on these occasions in line with theguidelines described above.

The following bacterial strains were used in these MIC determinations:

1) Pseudomonas aeruginosa UI-18: Wild-type, labeled as PA-7 in Tables 2and 3;

2) Acinetobacter baumannii/haemolyticus: Multidrug-resistant clinicalisolate labeled as AB-3167 in Tables 2 and 3;

3) Escherichia coli EC-1: VOGEL, mouse virulent labeled as EC-1 inTables 2 and 3;

4) Klebsiella pneumoniae: Ciprofloxacin-resistant isolate, expressesextended-spectrum beta-lactamases (ESBL), clinical isolate, labeled asKP-3700 in Tables 2 and 3.

Table 2, below, shows the results that were obtained with the finalproducts described in Examples 1-47. If a particular table entry is leftblank, then the data is not available at the current time.

Column 1 corresponds to the Example number, column 2 provides the IUPACname, column 3 provides the results from the LpxC enzyme assay describedabove, and columns 4-7 provide the MIC data as described above.

TABLE 2 PA: IC50 AB-3167 EC-1 KP-3700 PA-7 Example IUPACNAME (μM)(μg/mL) (μg/mL) (μg/mL) (μg/mL) 1 (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-0.00149 >64.0 >64.0 >64.0 32 tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 2(2R)-4-[5-fluoro-4-(2-fluoro-3- 0.000595 >64.0 0.25 1 0.25methylphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 3 (2R)-4-[4-(4-chlorophenyl)-5-fluoro-0.000325 64 0.25 1 0.25 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 4(2R)-4-[5-fluoro-4-(2-fluorophenyl)- 0.000717 >64.0 2 4 0.52-oxopyridin-1(2H)-yl]-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide5 (2R)-4-[4-(2,3-dihydro-1- 0.000822 >64.0 1 2 1benzofuran-5-yl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 6 (2R)-4-[4-(3,4-difluorophenyl)-5-0.000833 >64.0 1 2 0.5 fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 7(2R)-4-{5-fluoro-2-oxo-4-[4-(2,2,2- 0.000576 >64.0 0.25 2 1trifluoroethoxy)phenyl]pyridin-1(2H)- yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 8 (2R)-4-[4-(3,4-dihydro-2H-chromen-0.000377 >64.0 0.5 2 1 6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 19(2R)-4-{5-fluoro-4-[4- 0.00051 >64.0 0.25 1 0.5(methylthio)phenyl]-2-oxopyridin- 1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 10 (2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-0.000823 >64.0 0.25 1 1 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 11 (2R)-4-[5-fluoro-2-oxo-4-(4-0.000482 >64.0 0.125 0.5 0.5 propylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 12(2R)-4-{5-fluoro-2-oxo-4-[4- 0.00114 >64.0 4 16 4 (pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 13 (2R)-4-[5-fluoro-4-(3-methylphenyl)-0.00105 >64.0 1 4 1 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 14 (2R)-4-[5-fluoro-4-(4-fluoro-3-0.000758 >64.0 0.5 2 0.5 methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 15(2R)-4-{5-fluoro-4-[4-(oxetan-3- 0.00205 >64.0 16 32 16yloxy)phenyl]-2-oxopyridin-1(2H)- yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 16 (2R)-4-[4-(4-chloro-2-fluorophenyl)-0.000336 >64.0 0.25 1 0.5 5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 17(2R)-4-[5-fluoro-4-(2-fluoro-3- 0.0005 >64.0 0.5 1 1methoxyphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 18 (2R)-4-[5-fluoro-4-{4-[(trans-4-0.000463 >64.0 0.125 2 1 hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide19 (2R)-4-[5-fluoro-4-(3-fluoro-4- 0.000879 >64.0 2 4 1methoxyphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 20 (2R)-4-[5-fluoro-2-oxo-4-(4-0.000945 >64.0 0.125 0.5 1 pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 21(2R)-4-{5-fluoro-4-[4-(5- 0.000436 >64.0 0.125 0.5 1methoxypyrimidin-2-yl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 22 (2R)-4-{5-fluoro-4-[4-(4-methoxy-0.000181 >64.0 ≦0.0600 0.125 0.5 2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide 23(2R)-4-{5-fluoro-4-[4-(4-methyl-2H- 0.000287 >64.0 0.06 0.125 0.51,2,3-triazol-2-yl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 24(2R)-4-(5-fluoro-2-oxo-4-quinoxalin- 0.00123 >64.0 4 8 46-ylpyridin-1(2H)-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide25 (2R)-4-[5-fluoro-4-(3- 0.000412 >64.0 1 4 2methoxyphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 26 (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-0.0000743 >64.0 ≦0.0600 ≦0.0600 0.25 1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 27(2R)-4-[5-fluoro-4-(2-fluoro-4- 0.0000498 >64.0 0.25 0.5 0.5methoxyphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 28 (2R)-4-[5-fluoro-4-(4- 0.000564 >64.0 1 10.5 methoxyphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 29 (2R)-4-[5-fluoro-4-(4-methylphenyl)-0.000514 >64.0 0.5 1 0.5 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 30 (2R)-4-{5-fluoro-2-oxo-4-[4-0.000106 >64.0 0.25 2 0.5 (trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 31(2R)-4-[5-fluoro-4-(4-fluorophenyl)- 0.000213 >64.0 1 4 0.52-oxopyridin-1(2H)-yl]-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide32 (2R)-4-{5-fluoro-4-[4-(6- 0.0004 >64.0 ≦0.0600 1 1methoxypyridin-3-yl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 33 (2R)-4-{4-[4- 0.0000606 >64.0 0.52 0.5 (difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide 34(2R)-4-[5-fluoro-4-(4-methoxy-3- 0.000834 >64.0 0.25 2 0.5methylphenyl)-2-oxopyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 35 (2R)-4-{4-[4-(difluoromethoxy)-3-0.000589 >64.0 1 2 0.5 fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 36(2R)-4-{5-fluoro-4-[3-fluoro-4-(2H- 0.000398 >64.0 0.5 1 11,2,3-triazol-2-yl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 37(2R)-4-{5-fluoro-4-[3-methyl-4-(2H- >64.0 0.5 1 11,2,3-triazol-2-yl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 38 (2R)-4-(3,5-difluoro-2-oxo-4-0.00055 >64.0 1 2 0.5 phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 39(2R)-4-(5-fluoro-3-methoxy-2-oxo-4- 0.00807 64 4 8 8phenylpyridin-1(2H)-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide40 (2R)-4-(5-fluoro-3-hydroxy-2-oxo-4- >0.100 64 16 32 16phenylpyridin-1(2H)-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide41 (2R)-4-[5-fluoro-4-(4-isoxazol-3- 0.000237 16 0.5 0.25 0.5ylphenyl)-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 42 (2R)-4-{5-fluoro-4-[4-(1,3-oxazol-2-0.000328 >64.0 0.25 0.25 1 yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 43(2R)-4-[5-fluoro-4-(4-methylphenyl)- 0.000653 >64.0 0.25 1 0.52-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide-d_3_(—) 44 (2R)-4-[5-fluoro-4-(4-0.000664 >64.0 0.25 1 0.25 methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide-d_3_(—) 45(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro- 0.000547 >64.0 0.125 0.5 0.52-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide-d_5_(—) 46 (2R)-4-{4-[4-0.000229 >64.0 0.125 0.5 0.5 (cyclopropyloxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide 47(2R)-4-[4-(2,2-difluoro-1,3- >64.0 0.25 1 0.5benzodioxol-5-yl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 48 (2R)-4-[5-fluoro-2-oxo-4-0.000555 >64.0 0.06 0.25 0.5 (phenylethynyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 49(2R)-4-{5-Fluoro-2-oxo-4-[3-(1,3- 0.000758 >64 0.25 1 2thiazol-2-yloxy)phenyl]pyridin-1(2H)- yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Examples 50 to 125

The compounds named below can be made following the general proceduresoutlined in Examples 1-49 above. Products are typically derived from aSuzuki-Miyaura cross coupling, as described above utilizing theappropriate starting materials, with optional deprotection of a terminalhydroxamic acid protecting group. Methods used to describe the synthesisof the precursors or coupling partners such as boronic acids or estersare known to those skilled in the art.

In Table 3 below, column 1 corresponds to the Example number, column 2provides the IUPAC name, columns 3-6 provide in vitro biological datagenerated in the same manner as in Table 2, columns 7 and 8 provide theretention times and mass spectra generated via LCMS, using the methoddescribed below. All data is not currently available for all compounds,as indicated by a blank cell in Table 3.

The LCMS retention times reported in column 7 were generated in thefollowing manner:

-   Gradient:-   0.05% TFA 95:5 to 5:95 Water:ACN-   Flow rate: 1.3 mL/min-   Column dimensions: Acquity UPLC BEH C18 1.7 μm 2.1×30 mm.-   Run time: 1.1 minutes

TABLE 3 Example PA: IC50 AB-3167 EC-1 PA: UC12120 Retention NumberIUPACNAME (μM) (μg/mL) (μg/mL) (μg/mL) Time Mass 504-[5-fluoro-2-oxo-4-(3-oxo-2,3- 0.0682 >64.0 >64.0 >64.0 0.42 438.1dihydro-1H-isoindol-5-yl)pyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 51 4-[5-fluoro-4-(1H-indazol-6-yl)-0.0039 >64.0 >64.0 >64.0 0.49 423.1 2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 522-fluoro-4-{5-fluoro-1-[4- 0.0022 >64.0 64 32 0.45 458.1(hydroxyamino)-3-methyl-3- (methylsulfonyl)-4-oxobutyl]-2-oxo-1,2-dihydropyridin-4-yl}-N- methylbenzamide 534-[5-fluoro-4-(4-hydroxyphenyl)- 0.0042 >64.0 >64.0 64 0.46 3992-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide54 4-[4-(2,5-dimethoxyphenyl)-5- >0.100 >64.0 >64.0 >64.0 0.58 443.1fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 55 4-(5,5′-difluoro-2′-oxo-3,4′-0.0668 >64.0 >64.0 64 bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 564-[4-(3-chloro-5-fluorophenyl)-5- 0.0020 >64.0 8 2fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 57 4-[5-fluoro-4-(2-methyl-3-oxo-0.0210 >64.0 >64.0 >64.0 0.46 452.1 2,3-dihydro-1H-isoindol-5-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide 584-[4-(4-cyano-3-fluorophenyl)-5- 0.0026 >64.0 32 8fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 59 4-[5-fluoro-4-(4- 0.0010 >64.0 1 1methoxyphenyl)-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 60 4-{4-[4-(1-cyano-1- 0.0039 >64.0 32 4 0.61450.1 methylethyl)phenyl]-5-fluoro-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 614-[4-(3-acetamidophenyl)-5- >0.100 >64.0 >64.0 >64.0 0.47 440.1fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 62 4-[4-(3,5-difluoro-4- 0.0020 >64.0 4 20.62 449 methoxyphenyl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 62 4-[4-(3,5-difluorophenyl)-5-0.0031 >64.0 8 1 0.61 419 fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 644-[5-fluoro-4-(2-methyl-1-oxo- 0.0072 >64.0 >64.0 64 0.44 452.12,3-dihydro-1H-isoindol-5-yl)-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 654-(5′-fluoro-2′-oxo-3,4′-bipyridin- 0.0823 >64.0 >64.0 32 0.31 384.11′(2′H)-yl)-N-hydroxy-2-methyl- 2-(methylsulfonyl)butanamide 664-[4-(4-chloro-2-fluorophenyl)-5- 0.0008 64 0.5 0.5fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 67 4-[5-fluoro-4-(4-fluoro-3- 0.0045 64 16 40.59 431 methoxyphenyl)-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 68 4-{5-fluoro-1-[4-(hydroxyamino)-0.0343 >64.0 >64.0 >64.0 0.46 454.1 3-methyl-3-(methylsulfonyl)-4-oxobutyl]-2-oxo-1,2- dihydropyridin-4-yl}-N,N- dimethylbenzamide 694-(5′-fluoro-2-methoxy-2′-oxo- 0.0166 >64.0 64 83,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 70 4-(6-cyano-5′-fluoro-2′-oxo-3,4′-0.0333 >64.0 >64.0 64 0.47 409 bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 714-[5-fluoro-4-(3-methyl-3H- >0.100 >64.0 >64.0 >64.0 0.37 438.1imidazo[4,5-b]pyridin-6-yl)-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 724-(5-fluoro-4-furo[3,2-b]pyridin- 0.0348 >64.0 64 32 0.44 4246-yl-2-oxopyridin-1(2H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 73 4-(3′,5-difluoro-2-oxo-4,4′-0.0083 >64.0 >64.0 8 0.43 402 bipyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 74 4-[4-(4-cyano-3- 0.0059 >64.0 6416 methoxyphenyl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 75 4-(5′-fluoro-5,6-dimethoxy-2′-0.0454 >64.0 >64.0 >64.0 0.51 444.1 oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 764-[4-(4-ethoxyphenyl)-5-fluoro- 0.0011 >64.0 0.25 0.5 0.63 427.12-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide77 4-{4-[4-(2-cyanoethyl)phenyl]-5- 0.0026 >64.0 32 4 0.54 436.1fluoro-2-oxopyridin-1(2H)-yl}-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 78 4-(5-fluoro-2-oxo-4- 0.0028 >64.0 4 1 0.57383.1 phenylpyridin-1(2H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 79 4-[4-{4- 0.0359 >64.0 >64.0 16 0.37 440.1[(dimethylamino)methyl]phenyl}- 5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 804-(5′-fluoro-6-hydroxy-2′-oxo- >0.100 >64.0 >64.0 >64.0 0.35 4003,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 81 4-[4-(4-acetamidophenyl)-5- 0.0243 >64.064 32 0.45 440.1 fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 82 4-[4-(3-cyanophenyl)-5-fluoro-2-0.0130 >64.0 64 8 oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 834-(5,5′-difluoro-6-methyl-2′-oxo- 0.0275 >64.0 >64.0 32 0.49 416.13,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 84 4-{5-fluoro-1-[4-(hydroxyamino)-0.0145 >64.0 >64.0 >64.0 0.43 440.1 3-methyl-3-(methylsulfonyl)-4-oxobutyl]-2-oxo-1,2- dihydropyridin-4-yl}-N- methylbenzamide 854-[5′-fluoro-6-(hydroxymethyl)- >0.100 >64.0 >64.0 >64.0 0.32 414.12′-oxo-3,4′-bipyridin-1′(2′H)-yl]- N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 86 4-[5-fluoro-4-(4-fluorophenyl)-2-0.0017 >64.0 4 1 oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide 87 4-(5-fluoro-2-oxo-4-quinolin-3-0.0061 >64.0 16 8 0.46 434.1 ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 88 4-{5-fluoro-4-[4-(1- 0.0076 >64.016 4 0.59 441.1 methoxyethyl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 89 4-(5′-fluoro-6-methoxy-2′-oxo-0.0031 >64.0 8 2 3,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 90 4-(5-chloro-5′-fluoro-2′-oxo-2,4′-0.0125 >64.0 64 16 bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 91 4-{4-[4-(cyanomethyl)phenyl]-5-0.0023 >64.0 16 4 0.52 422.1 fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 924-(2′-ethoxy-5-fluoro-2-oxo-4,4′- 0.0057 >64.0 8 8 0.54 428.1bipyridin-1(2H)-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide 934-{5-fluoro-4-[3- 0.0142 >64.0 32 8 (methoxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide 944-[4-(2-cyanophenyl)-5-fluoro-2- 0.0323 32 8 32 0.52 408oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide 954-[4-(4-ethoxy-3-fluorophenyl)- 0.0012 64 1 2 0.63 445.15-fluoro-2-oxopyridin-1(2H)-yl]- N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 96 4-[5-fluoro-4-(2-methylquinolin-0.0108 >64.0 16 32 0.39 448.1 7-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 974-[4-(2,4-difluorophenyl)-5- 0.0012 >64.0 4 1 0.59 419fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 98 4-[4-(3,4-dimethoxyphenyl)-5- 0.0285 >64.064 32 0.53 443.1 fluoro-2-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 99 4-(6-ethoxy-5′-fluoro-2′-oxo- 0.0025 >64.02 2 3,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 100 4-[5-fluoro-4-(3- 0.0025 >64.0 4 2 0.58413.1 methoxyphenyl)-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 101 4-[4-(4-cyano-2- 0.0052 >64.0 64 8 0.55438.1 methoxyphenyl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 102 4-[4-(4-chloro-3-cyanophenyl)-0.0021 >64.0 4 4 0.6 442 5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 1034-[5-fluoro-4-(2-fluorophenyl)-2- 0.0014 >64.0 4 0.5 0.57 401.1oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide104 4-(5′-fluoro-2-isopropoxy-2′-oxo- >0.100 32 8 323,4′-bipyridin-1′(2′H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1054-{5-fluoro-4-[4-fluoro-3- >64.0 >64.0 >64.0 0.49 431.1(hydroxymethyl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1064-[5-fluoro-2-oxo-4-(2-pyrrolidin- 0.0568 >64.0 32 64 0.5 454.11-ylpyrimidin-5-yl)pyridin-1(2H)- yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 107 4-[4-(4-chlorophenyl)-5-fluoro-2-0.0010 >64.0 1 0.25 0.64 417 oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1084-[5-fluoro-2-oxo-4-(1-oxo-2,3- 0.0072 >64.0 >64.0 >64.0 0.4 438.1dihydro-1H-isoindol-5-yl)pyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 109 4-[4-(4-chloro-3- 0.0073 >64.0 32 32 0.56433 hydroxyphenyl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1104-{5-fluoro-4-[2- >0.100 >64.0 >64.0 >64.0 0.56 427.1(methoxymethyl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 111 4-[5-fluoro-4-(2-fluoro-3-0.0030 >64.0 4 4 0.61 445.1 methoxy-5-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide112 4-[4-(3-ethoxyphenyl)-5-fluoro- 0.0031 >64.0 2 42-oxopyridin-1(2H)-yl]-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide113 4-[5′-fluoro-2′-oxo-6- 0.0296 >64.0 >64.0 32 0.58 452(trifluoromethyl)-3,4′-bipyridin- 1′(2′H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 114 4-[4-(4-cyano-3-methylphenyl)-0.0013 >64.0 4 2 0.57 422.1 5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 115 4-{4-[2-0.0741 >64.0 32 32 0.48 428.1 (dimethylamino)pyrimidin-5-yl]-5-fluoro-2-oxopyridin-1(2H)-yl}- N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 116 4-[5-fluoro-4-(3-fluorophenyl)-2-0.0010 >64.0 4 1 0.58 401.1 oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 117 4-[4-(2,3-difluorophenyl)-5-0.0008 >64.0 2 0.5 0.59 419.1 fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 1184-[5-fluoro-4-(2-fluoro-3- 0.0007 >64.0 1 1 0.57 431.1methoxyphenyl)-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 119 4-[4-(3-cyano-5- 0.0508 >64.0 >64.0 640.57 438.1 methoxyphenyl)-5-fluoro-2- oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1204-[4-(2,3-dihydro-1-benzofuran- 0.0009 >64.0 2 1 0.57 425.15-yl)-5-fluoro-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1214-[5-fluoro-2-oxo-4-(1H-pyrazol- >64.0 >64.0 >64.03-yl)pyridin-1(2H)-yl]-N- hydroxy-2-methyl-2- (methylsulfonyl)butanamide122 4-{5-fluoro-4-[2-fluoro-3- 0.0024 0.46 431.1(hydroxymethyl)phenyl]-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1234-{4-[3-(2-amino-2- >64.0 >64.0 >64.0 0.43 440.1oxoethyl)phenyl]-5-fluoro-2- oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 1244-[4-(4-cyanophenyl)-5-fluoro-2- 0.0034 >64.0 32 8 0.53 408oxopyridin-1(2H)-yl]-N-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide125 4-[5-fluoro-4-(2- 0.0129 >64.0 64 8 0.57 413.1methoxyphenyl)-2-oxopyridin- 1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, in which: R¹ isrepresented by C₁-C₃ alkyl; R² is represented by hydrogen or C₁-C₃alkyl; R³ is represented by hydrogen, halogen, hydroxy, cyano,C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl or trifluoromethoxy; T isrepresented by ethynyl, optionally substituted (C₆-C₁₀)aryl oroptionally substituted heteroaryl; D is absent, or is represented by—(CH₂)_(r)—, —(CH₂)_(n)—O—(CH₂)_(p)—, or a bond; r is represented by theinteger 1, 2, or 3; n and p are each independently represented by theinteger 0, 1, or 2; E is absent, or is represented by a substituentselected from the group consisting of: i) (C₃-C₁₀)cycloalkyl, optionallysubstituted; ii) (C₆-C₁₀)aryl optionally substituted; iii) heteroaryl,optionally substituted; and iv) heterocyclic, optionally substituted;with the proviso that: 1) if E is absent, then D is also absent; 2) T isnot represented by unsubstituted phenyl; when E and D both are absent,R³ is hydrogen and R¹ and R² are each methyl.
 2. A compound according toclaim 1, or a pharmaceutically acceptable salt thereof in which R¹ andR² are each methyl.
 3. A compound according to claim 2, or apharmaceutically acceptable salt thereof in which R³ is hydrogen.
 4. Acompound according to claim 3, or a pharmaceutically acceptable saltthereof in which said compound is the R-enantiomer, substantially pure.5. A compound according to claim 4, or a pharmaceutically acceptablesalt thereof in which T is represented by phenyl which may be optionallysubstituted.
 6. A compound according to claim 4, or a pharmaceuticallyacceptable salt thereof in which D and E are both absent.
 7. A compoundaccording to claim 4, or a pharmaceutically acceptable salt thereof inwhich D is a bond.
 8. A compound according to claim 7, or apharmaceutically acceptable salt thereof in which E is represented bycyclohexyl, pyrimidinyl, triazolyl, pyridinyl, isoxazolyl, orcyclopropyl, any of which may be optionally substituted.
 9. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof in admixture with at leastone pharmaceutically acceptable excipient.
 10. A compound selected fromthe group consisting of(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(2-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(4-chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(2,3-dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(3,4-difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-2-oxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(3,4-dihydro-2H-chromen-6-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-2-oxo-4-(4-propylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-2-oxo-4-[4-(pentafluoro-6λ-sulfanyl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-fluoro-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(oxetan-3-yloxy)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(3-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-2-oxo-4-(4-pyrimidin-2-ylphenyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(5-methoxypyrimidin-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-(5-fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-2-oxo-4-[4-(trifluoromethoxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{4-[4-(difluoromethoxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-methoxy-3-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{4-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[3-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[3-methyl-4-(2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-(3,5-difluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-(5-fluoro-3-hydroxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-fluoro-4-[4-(1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-Fluoro-4-(4-trideuteromethylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-Fluoro-4-(4-trideuteromethoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(4-Pentadeuteroethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{4-[4-(cyclopropyloxy)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[4-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-[5-fluoro-2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;(2R)-4-{5-Fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-2-oxo-4-(3-oxo-2,3-dihydro-1H-isoindol-5-yl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(1H-indazol-6-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;2-fluoro-4-{5-fluoro-1-[4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl]-2-oxo-1,2-dihydropyridin-4-yl}-N-methylbenzamide;4-[5-fluoro-4-(4-hydroxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(2,5-dimethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5,5′-difluoro-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3-chloro-5-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-cyano-3-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{4-[4-(1-cyano-1-methylethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3-acetamidophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3,5-difluoro-4-methoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3,5-difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5′-fluoro-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(4-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-1-[4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl]-2-oxo-1,2-dihydropyridin-4-yl}-N,N-dimethylbenzamide;4-(5′-fluoro-2-methoxy-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(6-cyano-5′-fluoro-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5-fluoro-4-furo[3,2-b]pyridin-6-yl-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(3′,5-difluoro-2-oxo-4,4′-bipyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-cyano-3-methoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5′-fluoro-5,6-dimethoxy-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{4-[4-(2-cyanoethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-{4-[(dimethylamino)methyl]phenyl}-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5′-fluoro-6-hydroxy-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-acetamidophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5,5′-difluoro-6-methyl-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-1-[4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxobutyl]-2-oxo-1,2-dihydropyridin-4-yl}-N-methylbenzamide;4-[5′-fluoro-6-(hydroxymethyl)-2′-oxo-3,4′-bipyridin-1′(2′H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5-fluoro-2-oxo-4-quinolin-3-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-4-[4-(1-methoxyethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5′-fluoro-6-methoxy-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5-chloro-5′-fluoro-2′-oxo-2,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{4-[4-(cyanomethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(2′-ethoxy-5-fluoro-2-oxo-4,4′-bipyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-4-[3-(methoxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-ethoxy-3-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-methylquinolin-7-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(2,4-difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3,4-dimethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(6-ethoxy-5′-fluoro-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-cyano-2-methoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-chloro-3-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-(5′-fluoro-2-isopropoxy-2′-oxo-3,4′-bipyridin-1′(2′H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-4-[4-fluoro-3-(hydroxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-2-oxo-4-(2-pyrrolidin-1-ylpyrimidin-5-yl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-chlorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-2-oxo-4-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-chloro-3-hydroxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-4-[2-(methoxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-fluoro-3-methoxy-5-methylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5′-fluoro-2′-oxo-6-(trifluoromethyl)-3,4′-bipyridin-1′(2′H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-cyano-3-methylphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{4-[2-(dimethylamino)pyrimidin-5-yl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(3-fluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(2,3-difluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(3-cyano-5-methoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(2,3-dihydro-1-benzofuran-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[5-fluoro-2-oxo-4-(1H-pyrazol-3-yl)pyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{5-fluoro-4-[2-fluoro-3-(hydroxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-{4-[3-(2-amino-2-oxoethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;4-[4-(4-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; and4-[5-fluoro-4-(2-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compound,or a pharmaceutically acceptable salt thereof according to claim 10 inadmixture with at least one pharmaceutically acceptable excipient.
 12. Amethod for treating a Gram-negative bacterial infection in a patient,the method comprising administering a therapeutically effective amountof a compound or a pharmaceutically acceptable salt thereof according toclaim 10 to a patient in need of treatment thereof.
 13. The methodaccording to claim 12 wherein the Gram-negative bacterial infection iscaused by a Gram-negative bacteria selected from the group consisting ofAcinetobacter baumannii, Acinetobacter spp., Citrobacter spp.,Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli,Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens,Stenotrophomonas maltophilia, and Pseudomonas aeruginosa.
 14. The methodaccording to claim 12 wherein the Gram-negative bacterial infection isselected from the group consisting of nosocomial pneumonia, urinarytract infection, bacteremia, sepsis, skin infection, soft-tissueinfection, intraabdominal infection, lung infection, endocarditis,diabetic foot infection, osteomyelitis and central nervous systeminfection.